Preface

Lower urinary tract dysfunction (LUTD) is an umbrella diagnosis that covers the abnormalities of anatomy and function in the bladder, urethra, and, in men, the prostate. People with LUTD face a number of social, mental, and physical health effects due to the symptoms. Despite the increasing evidence in the assessment and management of lower urinary tract symptoms (LUTS), it remains a challenge to bridge the gap between research evidence and clinical practice. In this book, the authors demonstrate their understanding of how to apply the evidence to clinical practice from different aspects.

Based on epidemiological evidence, LUTS are heterogeneous between men and women, which is ascribed to the anatomical difference in the urethra between genders. Generally, pelvic organ prolapse (POP) is a common cause for elderly women to experience LUTS, while benign prostatic hyperplasia is the common cause for elderly men. Accurate evaluation and classification of POP is an important part of physical examination, which is certainly helpful for the development of a therapeutic strategy. Dr Priyanka Bhadana illustrates the assessment approaches of POP. This chapter includes many pictures that will help the readers understand POP.

Besides physical examination, urodynamic study has been playing an important role in the accurate assessment of LUTD. However, the majority of patients tend to prefer a noninvasive assessment compared to invasive urodynamics. Dr George Asafu Adjaye Frimpong and his colleagues present the infeasibility in using imaging modalities, including MRI, CT scan, ultrasound, PET, and fMRI, to assess the function of the lower urinary tract, instead of urodynamics. Not only are the innovative imaging techniques introduced, but also the advantages of each imaging modality for diagnosis of LUTD is interpreted in detail. Although these imaging modalities may not replace urodynamics completely, these approaches can be a substitute for urodynamics and provide useful information for clinicians.

Stress urinary incontinence (SUI) is one of the most common storage LUTS in females. Although the mid-urethral sling results in therapeutic success, it is still unclear how to predict the risk of SUI for individuals. Goran Mitulović introduces an innovative approach to detect potential SUI using proteomic analysis of the urine protein. Once a specific population group susceptible to SUI is identified, active surveillance could be provided as early as possible. In addition, behavior therapy, pelvic floor muscle training, and biofeedback, as a prevention strategy, may also be considered.

Nocturnal enuresis (NE) is a common condition in children. In general, the pathogenesis of NE mainly includes nocturnal polyuria, bladder capacity decline during nighttime, and arousal disorder. With the development of pharmacotherapy, a number of medications can be used to solve these problems. However, how to accurately assess and achieve precision medicine for each patient is still not easy. To help readers develop a proper therapeutic strategy for children with NE, Dr Zhou and her colleagues present current evidence in management of NE. Besides modern medicine, the complementary and alternative medicine approaches are also

**II**

**Chapter 7 109**

Lower Urinary Tract Symptoms (LUTS) and Sexual Function and

*by Charalampos Konstantinidis, Ioannis Eleftheropoulos* 

Dysfunction

*and Achileas Karafotias*

introduced. It is worth mentioning that Dr Zhou *et al.* show their research results in the chapter, which demonstrates the high level of evidence in the effectiveness of acupuncture in managing NE.

Urethral stricture is a common cause for men to experience lower urinary tract obstruction. Basically, the male urethra consists of the prostatic, membranous, bulbar, and penile urethra. In comparison with other segments, the penile urethral stricture is more complex to reconstruct. Prof. Martins uses a chapter to sketch out an overall perspective on penile urethroplasty. In it, he demonstrates both historical and innovative surgical procedures, which allows readers to obtain an outline of the surgery. Furthermore, he presents an algorithm of surgical reconstruction for different stricture sites, which provides a practical guide for clinicians.

Comorbidity has been the focus in the intervention studies for LUTS. Some recent surveys show a strong association between LUTS and male sexual dysfunction. Understanding the relationship may allow physicians to manage LUTS and sexual dysfunction simultaneously. Dr Konstantinidis and his colleagues bring us a chapter that discusses the comorbidity in the male population. Not only are the involved biochemical pathways described, but the therapeutic strategy is discussed based on current evidence.

In this book, experts and researchers from different countries present the latest evidence in diagnosis and treatment of LUTD. Although these chapters cannot cover all aspects of LUTD, they provide readers with important updates on LUTD. I believe that the more the doctors understand an disease, the more benefit the patients receive. This book is a key to help readers to open the door to LUTD. I hope the book can meet every reader's need.

> **Ran Pang** Department of Urology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China

> > **1**

Section 1

Introduction

Section 1 Introduction

**3**

**2. Clinical assessment for LUTS**

**Chapter 1**

*Ran Pang*

**1. Introduction**

at a Glance

Introductory Chapter: Lower

Lower urinary tract symptoms (LUTS) refer to a series of symptoms due to bladder or urethral dysfunction and are basically divided into three groups: storage, voiding, and post-micturition symptoms [1]. Of those, storage symptoms include urinary urgency, increased daytime frequency, nocturia, and different types of urinary incontinence. Voiding symptoms include slow stream, splitting or spraying of the urine stream, intermittency, hesitancy, straining to void, and terminal dribble. Post-micturition symptoms include feeling of incomplete emptying and post-micturition dribble. A number of epidemiological studies reported the prevalence of LUTS that varies from country to country. EPIC study performed a population-based, cross-sectional survey in Canada, Germany, Italy, Sweden, and the United Kingdom using computer-assisted telephone interview and showed the overall prevalence of LUTS was approximate 64.3% [2]. The EpiLUTS study investigated the prevalence of LUTS in the USA, United Kingdom, and Sweden according to an Internet-based survey. The results revealed that the prevalence of at least one LUTS in male and female population was 72.3 and 76.3%, respectively [3]. Another study demonstrated that the prevalence in South Korea was 68.5%, which is higher than 59% in Mainland China and 58.5% in Taiwan [4]. The heterogeneity in LUTS prevalence may derive from the difference in genetic, diet, and lifestyle factors for people in different countries. In terms of the gender difference, some studies showed that storage LUTS were more common in women than in men, while voiding and post-micturition LUTS were more common in men than in women [3, 4]. Furthermore, women have a higher proportion to experience storage and voiding LUTS simultaneously in comparison with men. The difference in LUTS between male and female may result from the different anatomy of urethra. Men have an additional organ, prostate, and a longer urethra compared to women, which means men are more likely to experience bladder outlet obstruction than women. Due to the gender difference, it appears to be reasonable to only focus on single-gender population when designing a clinical trial or research about LUTS. Recently a number of clinical trials and research studies have emerged in the assessment and management of LUTS. With the evidence increasing, it is worth considering how to apply these findings to clinical practice. We try to introduce the emerged evidence based on clinical practice from different aspects.

It remains a challenge how to make an accurate assessment for LUTS and identify the potential causes since the etiology of LUTS is diverse. According to EAU

Urinary Tract Dysfunction

#### **Chapter 1**

## Introductory Chapter: Lower Urinary Tract Dysfunction at a Glance

*Ran Pang*

#### **1. Introduction**

Lower urinary tract symptoms (LUTS) refer to a series of symptoms due to bladder or urethral dysfunction and are basically divided into three groups: storage, voiding, and post-micturition symptoms [1]. Of those, storage symptoms include urinary urgency, increased daytime frequency, nocturia, and different types of urinary incontinence. Voiding symptoms include slow stream, splitting or spraying of the urine stream, intermittency, hesitancy, straining to void, and terminal dribble. Post-micturition symptoms include feeling of incomplete emptying and post-micturition dribble. A number of epidemiological studies reported the prevalence of LUTS that varies from country to country. EPIC study performed a population-based, cross-sectional survey in Canada, Germany, Italy, Sweden, and the United Kingdom using computer-assisted telephone interview and showed the overall prevalence of LUTS was approximate 64.3% [2]. The EpiLUTS study investigated the prevalence of LUTS in the USA, United Kingdom, and Sweden according to an Internet-based survey. The results revealed that the prevalence of at least one LUTS in male and female population was 72.3 and 76.3%, respectively [3]. Another study demonstrated that the prevalence in South Korea was 68.5%, which is higher than 59% in Mainland China and 58.5% in Taiwan [4]. The heterogeneity in LUTS prevalence may derive from the difference in genetic, diet, and lifestyle factors for people in different countries. In terms of the gender difference, some studies showed that storage LUTS were more common in women than in men, while voiding and post-micturition LUTS were more common in men than in women [3, 4]. Furthermore, women have a higher proportion to experience storage and voiding LUTS simultaneously in comparison with men. The difference in LUTS between male and female may result from the different anatomy of urethra. Men have an additional organ, prostate, and a longer urethra compared to women, which means men are more likely to experience bladder outlet obstruction than women. Due to the gender difference, it appears to be reasonable to only focus on single-gender population when designing a clinical trial or research about LUTS. Recently a number of clinical trials and research studies have emerged in the assessment and management of LUTS. With the evidence increasing, it is worth considering how to apply these findings to clinical practice. We try to introduce the emerged evidence based on clinical practice from different aspects.

#### **2. Clinical assessment for LUTS**

It remains a challenge how to make an accurate assessment for LUTS and identify the potential causes since the etiology of LUTS is diverse. According to EAU

guideline, a number of conditions, including detrusor overactivity, underactive bladder, nocturnal polyuria, urethral stricture, etc., may contribute to male LUTS besides benign prostatic obstruction [5]. For female LUTS, increasing evidence shows that bladder outlet obstruction may play an important role in addition to pelvic floor dysfunction [6].

In general, physical examination can provide the helpful information for the etiological diagnosis of LUTS. Besides regular ones, bulbocavernosus reflex test is really useful to check the intactness of S2–S4 spinal reflex arc. Because sacral micturition center is located in S2–S4, this test is helpful to recognize the LUTS secondary to sacral or pudendal neuropathy. Additionally, the evaluation for pelvic floor function is essential for women with LUTS since it can identify the pelvic floor muscle tone, as well as the pelvic organ prolapse.

Traditionally, urodynamic study has been considered as a standard diagnostic tool for lower urinary tract dysfunction. Basically, urodynamic test contains filling cystometry (CMG) and pressure-flow studies (PFSs). The former is used to assess the storage function of the lower urinary tract, whereas the latter is used to evaluate the voiding function. Besides detecting bladder sensitivity, compliance, and detrusor overactivity, CMG can distinguish stress and urgency urinary incontinence. PFSs are normally used to diagnose bladder outlet obstruction. Furthermore, PFSs can also evaluate detrusor contraction, which is useful to find underactive bladder, a common cause of LUTS.

Despite advantages of urodynamic study, majority of patients tend to accept a noninvasive assessment compared to invasive urodynamic test. With the emergence of innovative imaging techniques, both anatomy and function of lower urinary tract can be assessed by noninvasive imaging approaches. In general, ultrasound is the most common technique to diagnose the lower urinary tract dysfunction. Some studies have shown that increased resistance of bladder contraction during the voiding phase in patients with bladder outlet obstruction (BOO) can result in an increase of bladder wall thickness (BWT), so can frequent detrusor overactive (DO) during the storage phase in patients with overactive bladder (OAB) [7, 8]. Based on this finding, a series of ultrasonographic parameters, including BWT, detrusor wall thickness (DWT), and ultrasound-estimated bladder weight (UEBW), have been used to diagnose BOO and DO. Furthermore, ultrasound strain imaging is also a successful method to evaluate LUTS since it can monitor the change in the BWT during micturition in real time. In addition, near-infrared spectroscopy is a functional imaging technique which can detect changes in the concentration of oxygenated hemoglobin and deoxygenated hemoglobin in the bladder wall and consequently identify the DO and BOO. In comparison with ultrasound, MRI may provide additional important clue for the diagnosis of lower urinary tract dysfunction. Brain functional MRI is helpful to detect the neurologic lesions demerging bladder control. Dynamic MRI is able to detect the pelvic organ prolapse, as well as the urethral hypermobility, which cannot be found by physical examination or static MRI.

#### **3. Management of LUTS**

Successful management for LUTS is based on the deep understanding on specific symptoms and accurate diagnosis on potential cause of LUTS. For patients with predominant voiding LUTS, it is essential to distinguish between BOO and underactive bladder (UAB). Once BOO is diagnosed clearly, α-blockers could be considered as the initial treatment. For male patients, if the BOO is secondary to significant enlarged prostate (>40 ml), 5α-reductase inhibitor is recommended to be added to shrink the prostate volume [5]. Moreover, there is increasing evidence to suggest

**5**

*Introductory Chapter: Lower Urinary Tract Dysfunction at a Glance*

gene therapy with myoblast injection, and neuromodulation [9].

factor, alarm therapy could be helpful in waking the children up.

Hospital, China Academy of Chinese Medical Sciences.

optimize the treatment effect.

**Acknowledgements**

In summary, accurate clinical assessment is the prerequisite to manage LUTS successfully. Only with the sufficient understanding in characteristics and potential causes of LUTS can an individual management strategy be developed, which may

This work was supported by Beijing Municipal Science and Technology Commission No. Z161100000516156 and grant 2014S292 from Guang'anmen

phosphodiesterase type 5 inhibitors (PDE5-Is) can relieve LUTS secondary to benign prostatic obstruction effectively though nitric oxide/cyclic guanosine monophosphate pathway (NO/cGMP). For patients who fail to respond to pharmacotherapy, minimal invasive surgical intervention, such as transurethral resection, could be an optional treatment. It is worth mentioning that urethral stricture is also a common cause of BOO and can be treated by urethral dilatation, internal urethrotomy, or urethroplasty depending on the characteristics of the stricture. The management of UAB, by contrast, is controversial because no regulatory approved specific therapy is available so far. Currently, the potential optional treatments for UAB include muscarinic agonists, regenerative therapy with mesenchymal stem cells or autologous muscle derived cells,

In terms of patients with predominant storage LUTS, OAB is the most common condition. Although behavioral interventions are recommended to be first-line treatment for OAB by guidelines, muscarinic antagonists and β3 agonists are normally used as the initial treatment in clinical practice. Once pharmacotherapy is unable to improve LUTS effectively, some invasive approaches including sacral neuromodulation, botulinum toxin type A intradetrusor injection, and posterior tibial nerve stimulation can be considered as the advanced therapeutic strategy. Urinary incontinence (UI) is another condition related to storage LUTS, and successful management mainly relies on the precise identification for different types. Urgency UI can be managed by the approaches similar with the ones for OAB. Mid-urethral sling has been mainstream intervention for stress UI since the consolidated theory was proposed by Dr. DeLancey in 1996. Compared to pure stress or urgency UI, mixed UI is more difficult to treat since its complex etiology. Today, the treatment only focuses on the main component of mixed UI. Besides conventional therapy, increasing high-level evidence demonstrates the effectiveness of complementary and alternative medicine on different types of UI [10, 11]. Nocturia is also a bothersome storage LUTS which not only can weaken patients' quality of life but also may increase the risk of mortality. Management of nocturia had been a controversial issue until the classification of nocturia was proposed, which allows clinicians to provide precision treatment for patients. It is reported that the main factors contributing to nocturia include nocturnal polyuria and bladder capacity decline during nighttime. The former can be managed by desmopressin or diuretics, whereas the latter can be treated by muscarinic antagonists and β3 agonists. It is important to differentiate nocturnal enuresis from nocturia in clinical practice, because both of them occur during the nighttime. The main difference between the two symptoms is whether the patient is accompanied by sleep arousal. Nocturnal enuresis occurs during sleep, while nocturia is presented in arousal. Moreover, nocturnal enuresis, also known as bed-wetting, is more likely to present in children, while nocturia is common in adults. Similar to the pathogenesis of nocturia, nocturnal polyuria, and bladder capacity decline during nighttime are the potential pathogenesis of nocturnal enuresis too. Besides, arousal disorder also plays an important role for the occurrence of nocturnal enuresis. For this

*DOI: http://dx.doi.org/10.5772/intechopen.90931*

#### *Introductory Chapter: Lower Urinary Tract Dysfunction at a Glance DOI: http://dx.doi.org/10.5772/intechopen.90931*

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

muscle tone, as well as the pelvic organ prolapse.

pelvic floor dysfunction [6].

a common cause of LUTS.

**3. Management of LUTS**

guideline, a number of conditions, including detrusor overactivity, underactive bladder, nocturnal polyuria, urethral stricture, etc., may contribute to male LUTS besides benign prostatic obstruction [5]. For female LUTS, increasing evidence shows that bladder outlet obstruction may play an important role in addition to

In general, physical examination can provide the helpful information for the etiological diagnosis of LUTS. Besides regular ones, bulbocavernosus reflex test is really useful to check the intactness of S2–S4 spinal reflex arc. Because sacral micturition center is located in S2–S4, this test is helpful to recognize the LUTS secondary to sacral or pudendal neuropathy. Additionally, the evaluation for pelvic floor function is essential for women with LUTS since it can identify the pelvic floor

Traditionally, urodynamic study has been considered as a standard diagnostic tool for lower urinary tract dysfunction. Basically, urodynamic test contains filling cystometry (CMG) and pressure-flow studies (PFSs). The former is used to assess the storage function of the lower urinary tract, whereas the latter is used to evaluate the voiding function. Besides detecting bladder sensitivity, compliance, and detrusor overactivity, CMG can distinguish stress and urgency urinary incontinence. PFSs are normally used to diagnose bladder outlet obstruction. Furthermore, PFSs can also evaluate detrusor contraction, which is useful to find underactive bladder,

Despite advantages of urodynamic study, majority of patients tend to accept a noninvasive assessment compared to invasive urodynamic test. With the emergence of innovative imaging techniques, both anatomy and function of lower urinary tract can be assessed by noninvasive imaging approaches. In general, ultrasound is the most common technique to diagnose the lower urinary tract dysfunction. Some studies have shown that increased resistance of bladder contraction during the voiding phase in patients with bladder outlet obstruction (BOO) can result in an increase of bladder wall thickness (BWT), so can frequent detrusor overactive (DO) during the storage phase in patients with overactive bladder (OAB) [7, 8]. Based on this finding, a series of ultrasonographic parameters, including BWT, detrusor wall thickness (DWT), and ultrasound-estimated bladder weight (UEBW), have been used to diagnose BOO and DO. Furthermore, ultrasound strain imaging is also a successful method to evaluate LUTS since it can monitor the change in the BWT during micturition in real time. In addition, near-infrared spectroscopy is a functional imaging technique which can detect changes in the concentration of oxygenated hemoglobin and deoxygenated hemoglobin in the bladder wall and consequently identify the DO and BOO. In comparison with ultrasound, MRI may provide

additional important clue for the diagnosis of lower urinary tract dysfunction. Brain functional MRI is helpful to detect the neurologic lesions demerging bladder control. Dynamic MRI is able to detect the pelvic organ prolapse, as well as the urethral hypermobility, which cannot be found by physical examination or static MRI.

Successful management for LUTS is based on the deep understanding on specific

symptoms and accurate diagnosis on potential cause of LUTS. For patients with predominant voiding LUTS, it is essential to distinguish between BOO and underactive bladder (UAB). Once BOO is diagnosed clearly, α-blockers could be considered as the initial treatment. For male patients, if the BOO is secondary to significant enlarged prostate (>40 ml), 5α-reductase inhibitor is recommended to be added to shrink the prostate volume [5]. Moreover, there is increasing evidence to suggest

**4**

phosphodiesterase type 5 inhibitors (PDE5-Is) can relieve LUTS secondary to benign prostatic obstruction effectively though nitric oxide/cyclic guanosine monophosphate pathway (NO/cGMP). For patients who fail to respond to pharmacotherapy, minimal invasive surgical intervention, such as transurethral resection, could be an optional treatment. It is worth mentioning that urethral stricture is also a common cause of BOO and can be treated by urethral dilatation, internal urethrotomy, or urethroplasty depending on the characteristics of the stricture. The management of UAB, by contrast, is controversial because no regulatory approved specific therapy is available so far. Currently, the potential optional treatments for UAB include muscarinic agonists, regenerative therapy with mesenchymal stem cells or autologous muscle derived cells, gene therapy with myoblast injection, and neuromodulation [9].

In terms of patients with predominant storage LUTS, OAB is the most common condition. Although behavioral interventions are recommended to be first-line treatment for OAB by guidelines, muscarinic antagonists and β3 agonists are normally used as the initial treatment in clinical practice. Once pharmacotherapy is unable to improve LUTS effectively, some invasive approaches including sacral neuromodulation, botulinum toxin type A intradetrusor injection, and posterior tibial nerve stimulation can be considered as the advanced therapeutic strategy. Urinary incontinence (UI) is another condition related to storage LUTS, and successful management mainly relies on the precise identification for different types. Urgency UI can be managed by the approaches similar with the ones for OAB. Mid-urethral sling has been mainstream intervention for stress UI since the consolidated theory was proposed by Dr. DeLancey in 1996. Compared to pure stress or urgency UI, mixed UI is more difficult to treat since its complex etiology. Today, the treatment only focuses on the main component of mixed UI. Besides conventional therapy, increasing high-level evidence demonstrates the effectiveness of complementary and alternative medicine on different types of UI [10, 11]. Nocturia is also a bothersome storage LUTS which not only can weaken patients' quality of life but also may increase the risk of mortality. Management of nocturia had been a controversial issue until the classification of nocturia was proposed, which allows clinicians to provide precision treatment for patients. It is reported that the main factors contributing to nocturia include nocturnal polyuria and bladder capacity decline during nighttime. The former can be managed by desmopressin or diuretics, whereas the latter can be treated by muscarinic antagonists and β3 agonists. It is important to differentiate nocturnal enuresis from nocturia in clinical practice, because both of them occur during the nighttime. The main difference between the two symptoms is whether the patient is accompanied by sleep arousal. Nocturnal enuresis occurs during sleep, while nocturia is presented in arousal. Moreover, nocturnal enuresis, also known as bed-wetting, is more likely to present in children, while nocturia is common in adults. Similar to the pathogenesis of nocturia, nocturnal polyuria, and bladder capacity decline during nighttime are the potential pathogenesis of nocturnal enuresis too. Besides, arousal disorder also plays an important role for the occurrence of nocturnal enuresis. For this factor, alarm therapy could be helpful in waking the children up.

In summary, accurate clinical assessment is the prerequisite to manage LUTS successfully. Only with the sufficient understanding in characteristics and potential causes of LUTS can an individual management strategy be developed, which may optimize the treatment effect.

#### **Acknowledgements**

This work was supported by Beijing Municipal Science and Technology Commission No. Z161100000516156 and grant 2014S292 from Guang'anmen Hospital, China Academy of Chinese Medical Sciences.

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

### **Author details**

Ran Pang Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China

\*Address all correspondence to: pangran2002@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**7**

*Introductory Chapter: Lower Urinary Tract Dysfunction at a Glance*

when investigating women with irritative urinary symptoms? BJOG.

[9] Chai TC, Kudze T. New therapeutic directions to treat underactive bladder. Investigative and Clinical Urology.

[10] Liu B et al. Electroacupuncture versus pelvic floor muscle training plus solifenacin for women with mixed urinary incontinence: A randomized noninferiority trial. Mayo Clinic Proceedings. 2019;**94**(1):54-65

electroacupuncture on urinary leakage among women with stress urinary incontinence: A randomized clinical trial. JAMA. 2017;**317**(24):2493-2501

2002;**109**(2):145-148

2017;**58**(Suppl 2):S99-S106

[11] Liu Z et al. Effect of

*DOI: http://dx.doi.org/10.5772/intechopen.90931*

[1] Abrams P et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourology and Urodynamics.

[2] Irwin DE et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: Results of the EPIC study. European Urology. 2006;**50**(6):1306-

[3] Coyne KS et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: Results from the epidemiology of LUTS (EpiLUTS) study. BJU International.

[4] Chapple C et al. Prevalence of lower urinary tract symptoms in China, Taiwan, and South Korea: Results from a cross-sectional, populationbased study. Advances in Therapy.

[5] Gratzke C et al. EAU guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. European

[6] Malde S et al. Female bladder outlet obstruction: Common symptoms masking an uncommon cause. Lower Urinary Tract Symptoms.

[7] Kuo HC. Measurement of detrusor

[8] Robinson D et al. Can ultrasound replace ambulatory urodynamics

wall thickness in women with overactive bladder by transvaginal and transabdominal sonography. International Urogynecology Journal and Pelvic Floor Dysfunction. 2009;**20**(11):1293-1299

Urology. 2015;**67**(6):1099-1109

**References**

2002;**21**(2):167-178

1314; discussion 1314-5

2009;**104**(3):352-360

2017;**34**(8):1953-1965

2019;**11**(1):72-77

*Introductory Chapter: Lower Urinary Tract Dysfunction at a Glance DOI: http://dx.doi.org/10.5772/intechopen.90931*

#### **References**

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

**6**

**Author details**

Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: pangran2002@gmail.com

provided the original work is properly cited.

Ran Pang

China

[1] Abrams P et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourology and Urodynamics. 2002;**21**(2):167-178

[2] Irwin DE et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: Results of the EPIC study. European Urology. 2006;**50**(6):1306- 1314; discussion 1314-5

[3] Coyne KS et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: Results from the epidemiology of LUTS (EpiLUTS) study. BJU International. 2009;**104**(3):352-360

[4] Chapple C et al. Prevalence of lower urinary tract symptoms in China, Taiwan, and South Korea: Results from a cross-sectional, populationbased study. Advances in Therapy. 2017;**34**(8):1953-1965

[5] Gratzke C et al. EAU guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. European Urology. 2015;**67**(6):1099-1109

[6] Malde S et al. Female bladder outlet obstruction: Common symptoms masking an uncommon cause. Lower Urinary Tract Symptoms. 2019;**11**(1):72-77

[7] Kuo HC. Measurement of detrusor wall thickness in women with overactive bladder by transvaginal and transabdominal sonography. International Urogynecology Journal and Pelvic Floor Dysfunction. 2009;**20**(11):1293-1299

[8] Robinson D et al. Can ultrasound replace ambulatory urodynamics

when investigating women with irritative urinary symptoms? BJOG. 2002;**109**(2):145-148

[9] Chai TC, Kudze T. New therapeutic directions to treat underactive bladder. Investigative and Clinical Urology. 2017;**58**(Suppl 2):S99-S106

[10] Liu B et al. Electroacupuncture versus pelvic floor muscle training plus solifenacin for women with mixed urinary incontinence: A randomized noninferiority trial. Mayo Clinic Proceedings. 2019;**94**(1):54-65

[11] Liu Z et al. Effect of electroacupuncture on urinary leakage among women with stress urinary incontinence: A randomized clinical trial. JAMA. 2017;**317**(24):2493-2501

**9**

Section 2

Assessment

Section 2

## Assessment

**11**

**Chapter 2**

**Abstract**

*Priyanka Bhadana*

in understandable terms.

diabetic neuropathy [2].

**1. Introduction**

**Keywords:** uterovaginal prolapse, POP-Q

Pelvic Organ Prolapse:

Examination and Assessment

Pelvic organ prolapse (POP) is a common, benign condition in women, and patient can present with complaints of vaginal bulge and pressure, voiding and defecatory, and sexual dysfunction, which may adversely affect quality of life. Although POP can occur in younger women, it is commonly seen in aging population with a prevalence of 45–50%. Older terms describing pelvic organ prolapse (e.g., cystocele, urethrocele, rectocele) have been replaced because they do not provide complete information regarding the structures on the other side of the vaginal bulge, especially in women who have had previous pelvic organ prolapse surgery. Therefore, a thorough history and performing a careful physical examination with dignity and care, using some basic tools that aid in the accurate evaluation of anatomical and functional defects, should be conducted. A standardized assessment system has been used to document findings which should explain everything

Pelvic organ prolapse (POP) is the herniation of the pelvic organs to or beyond the vaginal walls. Many women with prolapse experience symptoms that impact daily activities, sexual function, and exercise. The presence of POP can have a detrimental impact on body image and sexuality. Pelvic organ prolapse is an increasingly common condition seen with aging population with a prevalence of 41–50% of women above 40 years. The annual incidence of surgery for POP is within the range of 15–49 cases per 10,000 women years [1]. Pelvic floor defects result from attenuation of the supportive structures or by neuromuscular dysfunction due to obstetric trauma. Pregnancy itself, without vaginal birth, has been cited as a risk factor as well. Genital atrophy and hypoestrogenism also play important contributory roles in the pathogenesis of prolapse. However, the exact mechanisms are not completely understood. Prolapse may potentially result from pelvic tumors, sacral nerve disorders, and

Older terms describing pelvic organ prolapse (e.g., cystocele, urethrocele, rectocele) have been replaced because they do not provide complete information regarding the structures on the other side of the vaginal bulge, especially in women

who have had previous pelvic organ prolapse surgery.

#### **Chapter 2**

## Pelvic Organ Prolapse: Examination and Assessment

*Priyanka Bhadana*

#### **Abstract**

Pelvic organ prolapse (POP) is a common, benign condition in women, and patient can present with complaints of vaginal bulge and pressure, voiding and defecatory, and sexual dysfunction, which may adversely affect quality of life. Although POP can occur in younger women, it is commonly seen in aging population with a prevalence of 45–50%. Older terms describing pelvic organ prolapse (e.g., cystocele, urethrocele, rectocele) have been replaced because they do not provide complete information regarding the structures on the other side of the vaginal bulge, especially in women who have had previous pelvic organ prolapse surgery. Therefore, a thorough history and performing a careful physical examination with dignity and care, using some basic tools that aid in the accurate evaluation of anatomical and functional defects, should be conducted. A standardized assessment system has been used to document findings which should explain everything in understandable terms.

**Keywords:** uterovaginal prolapse, POP-Q

#### **1. Introduction**

Pelvic organ prolapse (POP) is the herniation of the pelvic organs to or beyond the vaginal walls. Many women with prolapse experience symptoms that impact daily activities, sexual function, and exercise. The presence of POP can have a detrimental impact on body image and sexuality. Pelvic organ prolapse is an increasingly common condition seen with aging population with a prevalence of 41–50% of women above 40 years. The annual incidence of surgery for POP is within the range of 15–49 cases per 10,000 women years [1]. Pelvic floor defects result from attenuation of the supportive structures or by neuromuscular dysfunction due to obstetric trauma. Pregnancy itself, without vaginal birth, has been cited as a risk factor as well. Genital atrophy and hypoestrogenism also play important contributory roles in the pathogenesis of prolapse. However, the exact mechanisms are not completely understood. Prolapse may potentially result from pelvic tumors, sacral nerve disorders, and diabetic neuropathy [2].

Older terms describing pelvic organ prolapse (e.g., cystocele, urethrocele, rectocele) have been replaced because they do not provide complete information regarding the structures on the other side of the vaginal bulge, especially in women who have had previous pelvic organ prolapse surgery.

Presently, the pelvis is divided into anterior, posterior, and middle or apical compartments. Following hysterectomy, prolapse of the vaginal apex with or without prolapse of the anterior and/or posterior vaginal wall is referred to as vault prolapse [2, 3].

### **2. Classification of pelvic organ prolapse**

Pelvic organ support is maintained by complex interactions between the vagina, levator ani muscle, and pelvic floor connective tissue. A system of three integrated levels of vaginal support has been described by De Lancey [1].


The prolapse is usually described according to the area of the vagina in which it occurs. Assumptions are often made about which organ is behind the vaginal wall that is prolapsing.

Anatomical classification according to vaginal wall:


#### **2.1 Shaw's classification**

	- Upper 2/3 cystocele
	- Lower 1/3 urethrocele
	- Upper 1/3 enterocele
	- Middle 1/3 rectocele
	- Lower 1/3 deficient perineum
	- Grade 0: Normal position
	- Grade 1: Descent into vagina not reaching the introitus

**13**

**Figure 1.**

*position.*

*Pelvic Organ Prolapse: Examination and Assessment DOI: http://dx.doi.org/10.5772/intechopen.91357*

○ Grade 2: Descent up to the introitus

○ Grade 3: Descent outside the introitus

• Uterovaginal prolapse usually occurs in nulliparous prolapse due to congenital

• Vaginouterine prolapse usually occurs in cases of prolapse resulting from

Pelvic organ prolapse quantification system refers to an objective, sitespecific system for describing, quantifying, and staging pelvic support in women (**Figure 1**). It provides a standardized tool for documenting, comparing, and communicating clinical findings with proven interobserver and intraobserver reliability. The POP-Q system gained the attention of the specialists all over the world, being approved by the International Continence Society (ICS), the American Urogynecologic Society (AUGS), and the Society of Gynecologic Surgeons for the description of female pelvic organ prolapse. It is the most common system used by gynecologists and urogynecologists, although other systems have been devised

The POP-Q may be an easier classification system to use in routine clinical practice. It was developed by the International Urogynecological Association to provide a less cumbersome exam tool [4]. The POP-Q stages (**Table 1**) prolapse

*POP-Q points. Aa, anterior vaginal wall 3 cm proximal to the urethral meatus (−3 cm to +3 cm); Ba,most distal position of the remaining upper anterior vaginal wall (−3 cm to +tvl); C, most distal edge of cervix or vaginal cuff scar; D, posterior fornix (n/a if posthysterectomy); Ap, posterior vaginal wall 3 cm proximal to the hymen (−3 cm to +3 cm); Bp, most distal position of the remaining upper posterior vaginal wall (−3 cm to + tvl); genital hiatus (gh), measured from the middle of external urethral meatus to the posterior midline hymen; perineal body (pb), measured from the posterior margin of gh to the middle of anal opening; total vaginal length (tvl), depth of the vagina when point D or C is reduced to normal* 

**3. Pelvic organ prolapse quantification system (POP-Q )**

○ Grade 4: Procidentia [2]

obstetrical trauma.

(**Figures 2**–**9**) [4].

weakness of cervical ligaments.

*Pelvic Organ Prolapse: Examination and Assessment DOI: http://dx.doi.org/10.5772/intechopen.91357*


*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

levels of vaginal support has been described by De Lancey [1].

• Level 1: The cardinal uterosacral ligament complex.

• Level 3: Urogenital diaphragm and the perineal body.

Anatomical classification according to vaginal wall:

• Middle: vault of the uterus (after hysterectomy).

**2. Classification of pelvic organ prolapse**

prolapse [2, 3].

that is prolapsing.

**2.1 Shaw's classification**

○ Upper 2/3 cystocele

○ Lower 1/3 urethrocele

○ Upper 1/3 enterocele

○ Middle 1/3 rectocele

○ Lower 1/3 deficient perineum

○ Grade 0: Normal position

○ Grade 1: Descent into vagina not reaching the introitus

• Anterior wall

• Posterior wall

• Uterine prolapse

Presently, the pelvis is divided into anterior, posterior, and middle or apical compartments. Following hysterectomy, prolapse of the vaginal apex with or without prolapse of the anterior and/or posterior vaginal wall is referred to as vault

Pelvic organ support is maintained by complex interactions between the vagina, levator ani muscle, and pelvic floor connective tissue. A system of three integrated

The prolapse is usually described according to the area of the vagina in which it occurs. Assumptions are often made about which organ is behind the vaginal wall

• Level 2: Midvaginal supports—pubocervical and rectovaginal fascia.

• Anterior: cystocele (bladder most common) and urethrocele (urethra).

• Posterior: rectocele (rectum) and enterocele (small bowel, omentum).

**12**


#### **3. Pelvic organ prolapse quantification system (POP-Q )**

Pelvic organ prolapse quantification system refers to an objective, sitespecific system for describing, quantifying, and staging pelvic support in women (**Figure 1**). It provides a standardized tool for documenting, comparing, and communicating clinical findings with proven interobserver and intraobserver reliability. The POP-Q system gained the attention of the specialists all over the world, being approved by the International Continence Society (ICS), the American Urogynecologic Society (AUGS), and the Society of Gynecologic Surgeons for the description of female pelvic organ prolapse. It is the most common system used by gynecologists and urogynecologists, although other systems have been devised (**Figures 2**–**9**) [4].

The POP-Q may be an easier classification system to use in routine clinical practice. It was developed by the International Urogynecological Association to provide a less cumbersome exam tool [4]. The POP-Q stages (**Table 1**) prolapse

#### **Figure 1.**

*POP-Q points. Aa, anterior vaginal wall 3 cm proximal to the urethral meatus (−3 cm to +3 cm); Ba,most distal position of the remaining upper anterior vaginal wall (−3 cm to +tvl); C, most distal edge of cervix or vaginal cuff scar; D, posterior fornix (n/a if posthysterectomy); Ap, posterior vaginal wall 3 cm proximal to the hymen (−3 cm to +3 cm); Bp, most distal position of the remaining upper posterior vaginal wall (−3 cm to + tvl); genital hiatus (gh), measured from the middle of external urethral meatus to the posterior midline hymen; perineal body (pb), measured from the posterior margin of gh to the middle of anal opening; total vaginal length (tvl), depth of the vagina when point D or C is reduced to normal position.*

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

**Figure 2.** *Point Aa being measured by graded spatula.*

**15**

**Figure 5.** *Point Ap.*

**Figure 4.** *Point C.*

*Pelvic Organ Prolapse: Examination and Assessment DOI: http://dx.doi.org/10.5772/intechopen.91357*

**Figure 3.** *Point Ba being measured by graded spatula.*

*Pelvic Organ Prolapse: Examination and Assessment DOI: http://dx.doi.org/10.5772/intechopen.91357*

**Figure 4.** *Point C.*

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

**14**

**Figure 3.**

**Figure 2.**

*Point Aa being measured by graded spatula.*

*Point Ba being measured by graded spatula.*

**Figure 5.** *Point Ap.* *Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

**Figure 6.** *Point Bp.*

**Figure 7.** *Point D.*

for the anterior and posterior vaginal walls, the apex/cuff of the vagina and the cervix. For women posthysterectomy, there are three stages; for women with an intact uterus, there are four. The exam is carried out similarly to the standard POP-Q exam, with a half speculum placed in the vagina to visualize the vaginal walls and cervix.

A disadvantage of POP-Q is that all points and measures are taken in the midline; as a consequence, the POP-Q does not reflect asymmetries and cannot be used to describe, for example, paravaginal defects. One has also to keep in mind that the POP-Q depends on the cooperation of the patient and to the strength of her cough or Valsalva maneuver; it is therefore unreasonable to assume that in an individual patient, the POP-Q will always be identical [4].

**17**

**Figure 9.** *Perineal body (Pb).*

**Figure 8.** *Genital hiatus (gh).*

*Pelvic Organ Prolapse: Examination and Assessment DOI: http://dx.doi.org/10.5772/intechopen.91357*

*Pelvic Organ Prolapse: Examination and Assessment DOI: http://dx.doi.org/10.5772/intechopen.91357*

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

for the anterior and posterior vaginal walls, the apex/cuff of the vagina and the cervix. For women posthysterectomy, there are three stages; for women with an intact uterus, there are four. The exam is carried out similarly to the standard POP-Q exam, with a half speculum placed in the vagina to visualize the vaginal

A disadvantage of POP-Q is that all points and measures are taken in the midline; as a consequence, the POP-Q does not reflect asymmetries and cannot be used to describe, for example, paravaginal defects. One has also to keep in mind that the POP-Q depends on the cooperation of the patient and to the strength of her cough or Valsalva maneuver; it is therefore unreasonable to assume that in an individual

**16**

walls and cervix.

**Figure 6.** *Point Bp.*

**Figure 7.** *Point D.*

patient, the POP-Q will always be identical [4].

**Figure 8.** *Genital hiatus (gh).*

**Figure 9.** *Perineal body (Pb).*


*Stage 0: Aa, Ap, Ba, Bp = −3 cm and C or D* ≤ *− (tvl − 2) cm. Stage l: Stage 0 criteria not met and leading edge < −1 cm. Stage ll: Leading edge* ≥ *−1 cm but* ≤ *+1 cm. Stage lll: Leading edge > +1 cm but < + (tvl − 2) cm. Stage lV: Leading edge* ≥ *+ (tvl −2) cm [3, 4].*

**Table 1.**

*Evaluation/staging of pelvic organ prolapse.*

#### **4. History**

Most patients with pelvic organ prolapse are asymptomatic. Seeing or feeling a bulge of tissue that protrudes to or past the vaginal opening is the most specific symptom.

#### **4.1 Bulge in the vagina**

During a well-woman examination, she should be asked regarding any obvious bulge seen or felt in vagina. The report of a bulge has an 81% positive predictive value and a 76% negative predictive value for pelvic organ prolapse.

Patient may complain of an increase in bulging and discomfort with progression of day [1]. Extensive standing, lifting, coughing, and physical exertion may increase patient awareness of discomfort in the pelvis, vagina, abdomen, and low back. Pelvic organ prolapse may progress with increasing body mass index. Weight loss does not reverse the prolapse.

#### **4.2 Vaginal discharge**

Vaginal discharge may be present in patients with complete uterine prolapse (i.e., procidentia) who have a decubitus ulcer of the cervix or vagina.

#### **4.3 Urinary symptoms**

Patients may have difficulty urinating—stress incontinence affects 40% of patients with pelvic organ prolapse; therefore, they should be asked about frequency, urgency, and sensation of incomplete emptying of the bladder, because they may not volunteer such information. Urinary outlet obstruction may occur because of the pressure on the urethra in anterior vaginal prolapse and sometimes in large posterior vaginal prolapse. Screening is advocated for urinary tract infection, postvoid residual urine volume, and the presence or absence of bladder sensation.

**19**

*Pelvic Organ Prolapse: Examination and Assessment DOI: http://dx.doi.org/10.5772/intechopen.91357*

compartment.

"splinting."

**4.5 Back pain**

**4.4 Bowel symptoms**

causes of pain should be ruled out.

**5.1 General physical examination**

**5.2 Abdominal examination**

**5.3 Local examination**

provocation test.

Valsalva shows levator ani damage.

and attenuated connective tissue present.

tantly, to recurrence after surgical repair [2].

require concomitant surgical correction [2, 3].

**4.6 Sexual discomfort**

**5. Examination**

Symptoms may not correlate with the location or severity of the prolapsed

Patients with posterior vaginal prolapse sometimes use manual pressure on the perineum or posterior vagina to help with defecation. These maneuvers are called

Though patients of prolapse attribute back and pelvic pain to their prolapse, very little evidence is available to show that this disorder causes pain, so other

Assessment will include weight, body mass index, and blood pressure, as well as assessment of any varicose veins or hypermobile joints, since these can be markers of a tendency to connective tissue laxity which predisposes to POP and, impor-

On examination of the abdomen, inspect for incisions of previous surgery (which may be associated with intra-abdominal adhesions affecting subsequent surgical approaches), and exclude masses or ascites. The presence of umbilical or other hernia can again indicate underlying connective tissue weakness and may

On inspection of the vulva, note the presence of any atrophy and whether there is any ulceration of prolapsed tissues that may require local estrogen therapy before surgery. Wide genital hiatus with visible vaginal walls or midline asymmetry on

For stress urinary incontinence, the patient needs to be examined with full bladder and asked to cough or strain, and leakage of urine confirms positive stress

On examination in lithotomy position, if there is visible vaginal bulge, look for vaginal wall rugosities which predict an intact fascial layer in the midline and a probable lateral defect, or if absent, it suggests a midline defect with only the skin

Sexual activity, body image, and quality of life may be affected [3].

Symptoms may not correlate with the location or severity of the prolapsed compartment.

#### **4.4 Bowel symptoms**

Patients with posterior vaginal prolapse sometimes use manual pressure on the perineum or posterior vagina to help with defecation. These maneuvers are called "splinting."

#### **4.5 Back pain**

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

II ≤1 cm proximal or distal to the plane of the hymen

IV Eversion of the lower genital tract is complete

**Pelvic organ prolapse quantification system**

I >1 cm above the hymen

*Stage ll: Leading edge* ≥ *−1 cm but* ≤ *+1 cm. Stage lll: Leading edge > +1 cm but < + (tvl − 2) cm. Stage lV: Leading edge* ≥ *+ (tvl −2) cm [3, 4].*

*Evaluation/staging of pelvic organ prolapse.*

vaginal length

*Stage 0: Aa, Ap, Ba, Bp = −3 cm and C or D* ≤ *− (tvl − 2) cm. Stage l: Stage 0 criteria not met and leading edge < −1 cm.*

**Stage Description** 0 No prolapse

Most patients with pelvic organ prolapse are asymptomatic. Seeing or feeling a bulge of tissue that protrudes to or past the vaginal opening is the most specific

III >1 cm below the plane of the hymen, but protrudes no farther than 2 cm less than the total

During a well-woman examination, she should be asked regarding any obvious bulge seen or felt in vagina. The report of a bulge has an 81% positive predictive

Patient may complain of an increase in bulging and discomfort with progression of day [1]. Extensive standing, lifting, coughing, and physical exertion may increase patient awareness of discomfort in the pelvis, vagina, abdomen, and low back. Pelvic organ prolapse may progress with increasing body mass index. Weight loss

Vaginal discharge may be present in patients with complete uterine prolapse

Patients may have difficulty urinating—stress incontinence affects 40% of patients with pelvic organ prolapse; therefore, they should be asked about frequency, urgency, and sensation of incomplete emptying of the bladder, because they may not volunteer such information. Urinary outlet obstruction may occur because of the pressure on the urethra in anterior vaginal prolapse and sometimes in large posterior vaginal prolapse. Screening is advocated for urinary tract infection, postvoid residual urine volume, and the presence or absence of bladder

value and a 76% negative predictive value for pelvic organ prolapse.

(i.e., procidentia) who have a decubitus ulcer of the cervix or vagina.

**18**

sensation.

**4. History**

**Table 1.**

*POP-Q staging criteria.*

symptom.

**4.1 Bulge in the vagina**

does not reverse the prolapse.

**4.2 Vaginal discharge**

**4.3 Urinary symptoms**

Though patients of prolapse attribute back and pelvic pain to their prolapse, very little evidence is available to show that this disorder causes pain, so other causes of pain should be ruled out.

#### **4.6 Sexual discomfort**

Sexual activity, body image, and quality of life may be affected [3].

#### **5. Examination**

#### **5.1 General physical examination**

Assessment will include weight, body mass index, and blood pressure, as well as assessment of any varicose veins or hypermobile joints, since these can be markers of a tendency to connective tissue laxity which predisposes to POP and, importantly, to recurrence after surgical repair [2].

#### **5.2 Abdominal examination**

On examination of the abdomen, inspect for incisions of previous surgery (which may be associated with intra-abdominal adhesions affecting subsequent surgical approaches), and exclude masses or ascites. The presence of umbilical or other hernia can again indicate underlying connective tissue weakness and may require concomitant surgical correction [2, 3].

#### **5.3 Local examination**

On inspection of the vulva, note the presence of any atrophy and whether there is any ulceration of prolapsed tissues that may require local estrogen therapy before surgery. Wide genital hiatus with visible vaginal walls or midline asymmetry on Valsalva shows levator ani damage.

For stress urinary incontinence, the patient needs to be examined with full bladder and asked to cough or strain, and leakage of urine confirms positive stress provocation test.

On examination in lithotomy position, if there is visible vaginal bulge, look for vaginal wall rugosities which predict an intact fascial layer in the midline and a probable lateral defect, or if absent, it suggests a midline defect with only the skin and attenuated connective tissue present.

#### **6. Examination in various positions**

#### **6.1 Standing position**

In some mild cases of vaginal wall and uterine prolapse, examination of the patient in standing position is the only way to explore it.

#### **6.2 Dorsal position**

Mostly for demonstration of uterine prolapse. Either the uterus will be obviously protruded or protrude when the patient is asked to strain.

#### **6.3 Sims' position**

In this position, the aim is to demonstrate the different types of vaginal wall prolapse. The patient is asked to lie on her left side at the edge of the table. The left leg is extended, while the right leg is flexed. Afterward, a sterile Sims' speculum is inserted into the vagina gently first to expose the anterior vaginal wall. Then it is pulled backward gradually to expose the posterior vaginal wall. Cystocele and rectocele are usually diagnosed by this examination.

#### **7. Per speculum examination**

Examination with a Cusco's bivalve speculum allows assessment of the cervix (including a Pap smear, if appropriate), but not of prolapse. The use of a Sims' speculum is required to carefully assess the anterior and posterior compartments and to assess the supports of the cervix or the vault if there has been a previous hysterectomy. If prolapse is visible at the vaginal introitus or on Valsalva maneuver, a systematic examination should be performed. With the patient in a supine position, a suitable sized vaginal speculum is introduced in the vagina to view the cervix or vaginal cuff, and the extent to which the cervix or the vaginal vault follows the speculum through and out of the vagina is noted, and the speculum is slowly removed while performing Valsalva maneuver.

To examine the anterior vaginal wall, the posterior vaginal wall is retracted with the fixed blade, and the extent of any anterior vaginal prolapse during the Valsalva maneuver is noted and vice versa to examine posterior vaginal wall. Any resulting prolapse is noted.

Decubitus ulcers are inspected and palpated. It is common to require sponge holding forceps to aid in support of the vaginal walls, as this can obscure the view.

#### **8. Per vaginal and rectovaginal examination**

Bimanual examination is performed to check the uterine size and mobility, as well as to exclude unsuspected adnexal pathology, such as ovarian tumors. This also allows an assessment of vaginal muscle tone. Rectal examination may distinguish rectocele from enterocele. Make sure you ask the woman to direct your attention to any other findings that she has noted, that you have not discovered, or that she wants to draw your attention to.

**21**

*Pelvic Organ Prolapse: Examination and Assessment DOI: http://dx.doi.org/10.5772/intechopen.91357*

evidence of pudendal neuropathy [4, 5]. Grading pelvic floor muscle strength:

1.No discernible contraction.

other despite resistance.

**9. Quantifying and documenting the findings**

• Type of examination table, speculum, and retractors

POP such as the POP-Q, Baden-Walker, or Shaw systems [4, 5].

perineum.

finger.

other.

poses [2].

• Patient position

• Bladder and rectal fullness

surgery. Testing for integrity of anal sphincter should be assessed for resting tone and voluntary squeeze and sensation around the vulva with the bulbocavernous reflex. (Stroking lateral to clitoris contraction of bilateral bulbocavernous muscle is observed.) The anocutaneous reflex (anal wink sign) is triggered by stroking the skin immediately surrounding the anus and observing a reflexive contraction of the external anal sphincter; this reflex should be elicited bilaterally. Absence of these reflexes is not always abnormal, and hyperreflexia or asymmetry may in fact be more suggestive of a neurologic etiology. Crude sensory testing is advocated for

2.Barely palpable, flickering contraction, not visible on inspection of the

upward and forward movement, visible on the perineal surface.

3.Weak, distinctly palpable contraction, felt as slight pressure on the examining

4.Moderate muscle strength, distinct pressure on the examining finger, palpable

5.Good muscle strength, elevation possible against slight resistance, circular pressure can be felt around the examining finger. During simultaneous examination by the index and middle finger, these are pressed against each

6.Very strong muscle strength, contraction possible against vigorous resis-

A full description of the examination is recorded, including the following:

It is important to note and document any episodes of urinary, fecal, or flatal incontinence that occur during the examination. The findings of the examination should be recorded using a quantitative and reproducible method for recording

tance, with suction-type effect on the examining finger. During simultaneous examination by the index and middle finger, these are pressed against each

Digital examination makes it possible to distinguish between the left and right side of the levator ani. It is capable of quantifying strength, strength endurance, fast contraction, and fast contraction endurance for clinical pur-

Bonney's stress test is performed following reduction of prolapsed. If test is positive, incontinence surgery should be performed at the time of prolapse *Pelvic Organ Prolapse: Examination and Assessment DOI: http://dx.doi.org/10.5772/intechopen.91357*

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

patient in standing position is the only way to explore it.

protruded or protrude when the patient is asked to strain.

rectocele are usually diagnosed by this examination.

removed while performing Valsalva maneuver.

**8. Per vaginal and rectovaginal examination**

wants to draw your attention to.

**7. Per speculum examination**

In some mild cases of vaginal wall and uterine prolapse, examination of the

Mostly for demonstration of uterine prolapse. Either the uterus will be obviously

In this position, the aim is to demonstrate the different types of vaginal wall prolapse. The patient is asked to lie on her left side at the edge of the table. The left leg is extended, while the right leg is flexed. Afterward, a sterile Sims' speculum is inserted into the vagina gently first to expose the anterior vaginal wall. Then it is pulled backward gradually to expose the posterior vaginal wall. Cystocele and

Examination with a Cusco's bivalve speculum allows assessment of the cervix (including a Pap smear, if appropriate), but not of prolapse. The use of a Sims' speculum is required to carefully assess the anterior and posterior compartments and to assess the supports of the cervix or the vault if there has been a previous hysterectomy. If prolapse is visible at the vaginal introitus or on Valsalva maneuver, a systematic examination should be performed. With the patient in a supine position, a suitable sized vaginal speculum is introduced in the vagina to view the cervix or vaginal cuff, and the extent to which the cervix or the vaginal vault follows the speculum through and out of the vagina is noted, and the speculum is slowly

To examine the anterior vaginal wall, the posterior vaginal wall is retracted with the fixed blade, and the extent of any anterior vaginal prolapse during the Valsalva maneuver is noted and vice versa to examine posterior vaginal wall. Any resulting

Decubitus ulcers are inspected and palpated. It is common to require sponge holding forceps to aid in support of the vaginal walls, as this can obscure the

Bimanual examination is performed to check the uterine size and mobility, as well as to exclude unsuspected adnexal pathology, such as ovarian tumors. This also allows an assessment of vaginal muscle tone. Rectal examination may distinguish rectocele from enterocele. Make sure you ask the woman to direct your attention to any other findings that she has noted, that you have not discovered, or that she

Bonney's stress test is performed following reduction of prolapsed. If test is positive, incontinence surgery should be performed at the time of prolapse

**6. Examination in various positions**

**6.1 Standing position**

**6.2 Dorsal position**

**6.3 Sims' position**

prolapse is noted.

view.

**20**

surgery. Testing for integrity of anal sphincter should be assessed for resting tone and voluntary squeeze and sensation around the vulva with the bulbocavernous reflex. (Stroking lateral to clitoris contraction of bilateral bulbocavernous muscle is observed.) The anocutaneous reflex (anal wink sign) is triggered by stroking the skin immediately surrounding the anus and observing a reflexive contraction of the external anal sphincter; this reflex should be elicited bilaterally. Absence of these reflexes is not always abnormal, and hyperreflexia or asymmetry may in fact be more suggestive of a neurologic etiology. Crude sensory testing is advocated for evidence of pudendal neuropathy [4, 5].

Grading pelvic floor muscle strength:


Digital examination makes it possible to distinguish between the left and right side of the levator ani. It is capable of quantifying strength, strength endurance, fast contraction, and fast contraction endurance for clinical purposes [2].

#### **9. Quantifying and documenting the findings**

A full description of the examination is recorded, including the following:


It is important to note and document any episodes of urinary, fecal, or flatal incontinence that occur during the examination. The findings of the examination should be recorded using a quantitative and reproducible method for recording POP such as the POP-Q, Baden-Walker, or Shaw systems [4, 5].

### **10. Further evaluation**

Further studies depend on the symptoms, stage of prolapse, and treatment plan. If needed for definitive treatment planning, urodynamic studies can help in identifying those patients with lower urinary tract symptoms (urinary incontinence) who are most likely to get benefit from surgery or may require stress incontinence surgery. Patients with defecatory symptoms and/or fecal incontinence may need anal manometry and endoanal ultrasonography [5].

### **11. Conclusion**

Taking a thorough history and performing a careful physical examination of women who are referred help in the assessment of prolapse. Examination should be carried out with dignity and care, using some basic tools that aid in the accurate evaluation of anatomical and functional defects. A standardized assessment system has been used to document findings which should explain everything in understandable terms.

#### **Author details**

Priyanka Bhadana ABVIMS and RML Hospital, New Delhi, India

\*Address all correspondence to: docpriyanka89@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**23**

*Pelvic Organ Prolapse: Examination and Assessment DOI: http://dx.doi.org/10.5772/intechopen.91357*

[1] Shaw R, Luesley D, Monga A, editors. Urogynaecology Section. Gynaecology, 4th ed. London: Churchill Livingstone;

[2] Bordman R, Telner D, et al. Stepby-step approach to managing pelvic organ prolapse. Can Fam Physician.

[3] Kuncharapu I, Majeroni BA. Pelvic organ prolapsed Am fam physician.

[4] Kieren W, Andrew F. Prolapse assessment. Int urogynecol J.

[5] ACOG Committee on practice bulletins—gynecology. ACOG practice bulletin no. 85: Pelvic organ prolapse. Obstetrics and Gynecology.

2007;**53**(3):485-487

2010;**81**(9):1111-1117

2007;**110**(3):717-729

2014;**16**(1):35

2010

**References**

*Pelvic Organ Prolapse: Examination and Assessment DOI: http://dx.doi.org/10.5772/intechopen.91357*

### **References**

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

anal manometry and endoanal ultrasonography [5].

Further studies depend on the symptoms, stage of prolapse, and treatment plan. If needed for definitive treatment planning, urodynamic studies can help in identifying those patients with lower urinary tract symptoms (urinary incontinence) who are most likely to get benefit from surgery or may require stress incontinence surgery. Patients with defecatory symptoms and/or fecal incontinence may need

Taking a thorough history and performing a careful physical examination of women who are referred help in the assessment of prolapse. Examination should be carried out with dignity and care, using some basic tools that aid in the accurate evaluation of anatomical and functional defects. A standardized assessment system has been used to document findings which should explain everything in under-

**10. Further evaluation**

**11. Conclusion**

standable terms.

**22**

**Author details**

Priyanka Bhadana

ABVIMS and RML Hospital, New Delhi, India

provided the original work is properly cited.

\*Address all correspondence to: docpriyanka89@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Shaw R, Luesley D, Monga A, editors. Urogynaecology Section. Gynaecology, 4th ed. London: Churchill Livingstone; 2010

[2] Bordman R, Telner D, et al. Stepby-step approach to managing pelvic organ prolapse. Can Fam Physician. 2007;**53**(3):485-487

[3] Kuncharapu I, Majeroni BA. Pelvic organ prolapsed Am fam physician. 2010;**81**(9):1111-1117

[4] Kieren W, Andrew F. Prolapse assessment. Int urogynecol J. 2014;**16**(1):35

[5] ACOG Committee on practice bulletins—gynecology. ACOG practice bulletin no. 85: Pelvic organ prolapse. Obstetrics and Gynecology. 2007;**110**(3):717-729

**25**

**Chapter 3**

**Abstract**

or detrusor overactivity (DO).

**1. Introduction**

peripheral organs [4].

Diagnostic Potential of Imaging

Modalities in the Assessment of

*George Asafu Adjaye Frimpong, Evans Aboagye* 

*and Akosua Asafu-Adjaye Frimpong*

Lower Urinary Tract Dysfunctions

Lower urinary tract dysfunction (LUTD) is common in both men and women, and the incidence and prevalence increases as people age. Commonly observed symptoms of LUTD include nocturia, urgency, urinary incontinence and frequency of voiding. Recognizing the key role accurate monitoring and evaluation of LUTD play in the day-to-day assessment of the condition, this chapter will explore the diagnostic capabilities of imaging modalities including MRI, ultrasound and fluoroscopy in assessing bladder wall thickness (BWT), detrusor wall thickness (DWT) and estimation of bladder weight both in real-time and static positions, and finally analyze their suitability as surrogates for bladder outlet obstruction (BOO)

**Keywords:** lower urinary tract dysfunction, bladder, MRI, ultrasound, PET

The lower urinary tract (LUT), consisting of the urinary bladder and urethra, functions to store and expel urine in a controlled and coordinated manner [1, 2]. This key function is dependent upon neural circuits located in the central and peripheral nervous system (CNS) (brain, peripheral ganglia, spinal cord and brain) [1], thus distinguishing LUT from other visceral structures such as cardiovascular system and gastrointestinal tract, that are able to sustain a certain level of activity even after elimination of extrinsic neural input [3]. Considering the fact that control over urine storage and voiding is somehow complex and also dependent on neurological elements widely distributed in anatomical terms, the function of LUT can be affected by a myriad of neurological diseases and disorders of the

Lower urinary tract dysfunctions (LUTD) may thus result from lesions affecting the brain, suprasacral spinal cord and sacral spinal cord or peripheral nerve [5]. Lesions affecting the suprasacral or spinal pathways affect the storage phase, leading to reduced bladder capacity and detrusor overactivity, which is characterized by varying degrees of urinary frequency, urgency, incontinence and nocturia, while lesions of the sacral spinal cord pathways result in voiding dysfunction, associated with non-relaxing sphincter and/or absent or poorly sustained detrusor contractions [6]. As a result, functional disorders such as bladder outlet obstruction

#### **Chapter 3**

## Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract Dysfunctions

*George Asafu Adjaye Frimpong, Evans Aboagye and Akosua Asafu-Adjaye Frimpong*

#### **Abstract**

Lower urinary tract dysfunction (LUTD) is common in both men and women, and the incidence and prevalence increases as people age. Commonly observed symptoms of LUTD include nocturia, urgency, urinary incontinence and frequency of voiding. Recognizing the key role accurate monitoring and evaluation of LUTD play in the day-to-day assessment of the condition, this chapter will explore the diagnostic capabilities of imaging modalities including MRI, ultrasound and fluoroscopy in assessing bladder wall thickness (BWT), detrusor wall thickness (DWT) and estimation of bladder weight both in real-time and static positions, and finally analyze their suitability as surrogates for bladder outlet obstruction (BOO) or detrusor overactivity (DO).

**Keywords:** lower urinary tract dysfunction, bladder, MRI, ultrasound, PET

#### **1. Introduction**

The lower urinary tract (LUT), consisting of the urinary bladder and urethra, functions to store and expel urine in a controlled and coordinated manner [1, 2]. This key function is dependent upon neural circuits located in the central and peripheral nervous system (CNS) (brain, peripheral ganglia, spinal cord and brain) [1], thus distinguishing LUT from other visceral structures such as cardiovascular system and gastrointestinal tract, that are able to sustain a certain level of activity even after elimination of extrinsic neural input [3]. Considering the fact that control over urine storage and voiding is somehow complex and also dependent on neurological elements widely distributed in anatomical terms, the function of LUT can be affected by a myriad of neurological diseases and disorders of the peripheral organs [4].

Lower urinary tract dysfunctions (LUTD) may thus result from lesions affecting the brain, suprasacral spinal cord and sacral spinal cord or peripheral nerve [5]. Lesions affecting the suprasacral or spinal pathways affect the storage phase, leading to reduced bladder capacity and detrusor overactivity, which is characterized by varying degrees of urinary frequency, urgency, incontinence and nocturia, while lesions of the sacral spinal cord pathways result in voiding dysfunction, associated with non-relaxing sphincter and/or absent or poorly sustained detrusor contractions [6]. As a result, functional disorders such as bladder outlet obstruction secondary to prostatic enlargement, overactive bladder and urinary incontinence are common, as are prostate and bladder carcinoma [7].

Clinical assessment of LUDT may include tests such as post-void residual volume measurement, renal ultrasound, uroflowmetry, urethrocystoscopy, neurophysiology and urodynamics depending on the indication [6]. Furthermore, urodynamic tests including filling cystometry and pressure flow study are considered as the gold standard methods for diagnosing detrusor overactivity (DO) and bladder outlet obstruction (BOO) respectively. The key issue with the urodynamic techniques is that, they are invasive and hence are associated with potential patient morbidity [8]. Therefore, there have been efforts over the years toward developing non-invasive techniques such as ultrasound, magnetic resonance imaging (MRI), fluoroscopy and near-infrared spectroscopy, with the potential of serving as suitable surrogates for diagnosing BOO and DO. Recognizing the key role these imaging modalities play in accurate monitoring and evaluation of LUTD, this chapter set out to explore their diagnostic potential in LUTD and finally examine their suitability as surrogates for the urodynamic tests.

#### **2. The lower urinary tract**

The lower urinary tract (LUT) consists of urinary bladder and urethra, and also includes the prostate in males. These organs are actively involved in the involuntary storage of urine formed in the upper urinary tract and the voluntary expulsion of urine at a suitable place and time [7]. The effectiveness of these functions depend on the activity of striated and smooth muscles in the bladder, urethra and external urethral sphincter, which is in turn controlled by neural circuits in the spinal cord, peripheral ganglia and brain [4]. Owning to the differences in sexual function and pelvic anatomy, there are considerable differences in the anatomy of LUT in males and females.

The bladder is a hollow organ located within the pelvis. Its wall consists of five layers from inside out, and the muscle of the bladder, the detrusor, is composed of smooth muscle fibers [9]. The wall thickness of the bladder decreases from 2 cm to 2 mm during expansion. The principal function of the bladder is that of a reservoir, storing urine at lower pressures, even with large filling volumes. The normal bladder holds 200–500 ml urine, and for imaging assessment, a full bladder is preferred for visualization. Due to the visco-elastic properties of the bladder wall and the inhibition of the filling phase detrusor contractions, the bladder is compliant and the pressure inside usually remain low [10]. In the clinical assessment of images of the LUT, it is important to note the close relation between the anterior vaginal wall and the urethra in women and between seminal vesicles and prostate and posterior urethra and the bladder base in men [11].

#### **2.1 Lower urinary tract dysfunction (LUTD)**

The primary physiological functions of the LUT are the storage of urine (at relatively low pressure) and its voiding (expulsion) at appropriate time. LUT dysfunction is a common problem, and the prevalence increases with ageing. The term "dysfunction" indicates an abnormality in the physiology of the lower urinary tract, including urinary sphincter, associated nervous system, bladder neck and detrusor muscle. This may result in failure to store urine, failure to empty or a combination of both [12]. Lower urinary tract symptoms can thus be divided into storage phase symptoms, voiding phase symptoms and postmicturition symptoms. These symptoms can be caused by various types of bladder dysfunctions

**27**

*Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract…*

such as overactive bladder, underactive bladder, urinary tract infections and neurogenic disorders [13]. Storage symptoms include increased nocturia, daytime frequency, urgency and incontinence. Voiding symptoms include splitting or spraying, slow stream, intermittency, hesitancy, straining and terminal dribble. Post micturition symptoms include a feeling of incomplete emptying and post

Voiding as intended by nature should result in complete emptying of the bladder. This depends on a coordinated contraction of the detrusor smooth muscle with a simultaneous lowering of bladder outlet resistance. Distortion, compression or occlusion of the outlet of the bladder obstructs urine flow during expulsion, with attendant characteristic symptoms of dribbling, poor stream, incomplete emptying and hesitancy. Bladder outlet obstruction (BOO) is an indication of the existence of abnormal tissue which modifies the configuration of the bladder outlet through distortion, compression or occlusion, thus impeding the urine flow at the time of expulsion. Accompanying urine symptoms include slow stream, intermittent stream, hesitancy, straining to void, terminal dribble, post-micturition dribble and

These LUT symptoms are caused by a variety of different pathologies. The commonest processes responsible for BOO in men are benign prostatic enlargement (BPE) or urethral stricture disease [15]. For lesser degrees of obstruction, the symptomatic consequences may be slight, owing to compensatory responses, such as enhanced bladder contractility. However, a potential feature of BPE is the progression of obstruction with ageing, which leads to evident expulsion and post-micturition LUT symptoms. Also, the emergence of LUT symptoms point to relative inadequacy in the expulsive capacity of the bladder, which may be a consequence of detrusor underactivity. Detrusor underactivity is characterized by a contraction of reduced duration and/or strength, thus resulting in failure to achieve complete bladder emptying within regular time span and/or prolonged bladder emptying. The variables of detrusor contraction strength, contraction duration and outlet obstruction severity leads to varied clinical features of BOO. The basis of obstruction in females may be bladder neck distortion, urethral compression or luminal occlusion and functional issues [16]. However, in women, due to difficulty in assessing bladder contractility, there is difficulty in arriving at decisions on issues regarding diagnosis of BOO [15]. Diagnosis of BOO can be made based on invasive urodynamic study, such as videourodynamic study or pressure flow study. Also, a noninvasive method to diagnose BOO is needed for more accurate treatment [17].

*2.1.2 Overactive bladder (OAB) and detrusor overactivity (DO)*

the sensation of urgency from the urge to void [19].

According to the International Continence Society (ICS), overactive bladder (OAB) is defined as a complex of urgency, usually with increased daytime frequency and nocturia, with (OAB wet) or without (OAB dry) urinary incontinence. Urgency is the key symptom of OAB, and it is a sudden compelling desire to pass urine, which is difficult to defer [18]. In diagnosing OAB, it is assumed that conflicting issues such as, urinary tract infections are excluded. OAB might be because of increased bladder sensation or detrusor overactivity (DO). Confusion usually exists between these two disease states because patients usually cannot differentiate

DO is an urodynamic observation characterized by involuntary detrusor contractions during the filling phase that may be provoked or spontaneous. The ICS

*DOI: http://dx.doi.org/10.5772/intechopen.86934*

*2.1.1 Bladder outlet obstruction (BOO)*

feeling of incomplete emptying [15].

micturition dribble [14].

#### *Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract… DOI: http://dx.doi.org/10.5772/intechopen.86934*

such as overactive bladder, underactive bladder, urinary tract infections and neurogenic disorders [13]. Storage symptoms include increased nocturia, daytime frequency, urgency and incontinence. Voiding symptoms include splitting or spraying, slow stream, intermittency, hesitancy, straining and terminal dribble. Post micturition symptoms include a feeling of incomplete emptying and post micturition dribble [14].

#### *2.1.1 Bladder outlet obstruction (BOO)*

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

are common, as are prostate and bladder carcinoma [7].

as surrogates for the urodynamic tests.

urethra and the bladder base in men [11].

**2.1 Lower urinary tract dysfunction (LUTD)**

**2. The lower urinary tract**

and females.

secondary to prostatic enlargement, overactive bladder and urinary incontinence

Clinical assessment of LUDT may include tests such as post-void residual volume measurement, renal ultrasound, uroflowmetry, urethrocystoscopy, neurophysiology and urodynamics depending on the indication [6]. Furthermore, urodynamic tests including filling cystometry and pressure flow study are considered as the gold standard methods for diagnosing detrusor overactivity (DO) and bladder outlet obstruction (BOO) respectively. The key issue with the urodynamic techniques is that, they are invasive and hence are associated with potential patient morbidity [8]. Therefore, there have been efforts over the years toward developing non-invasive techniques such as ultrasound, magnetic resonance imaging (MRI), fluoroscopy and near-infrared spectroscopy, with the potential of serving as suitable surrogates for diagnosing BOO and DO. Recognizing the key role these imaging modalities play in accurate monitoring and evaluation of LUTD, this chapter set out to explore their diagnostic potential in LUTD and finally examine their suitability

The lower urinary tract (LUT) consists of urinary bladder and urethra, and also includes the prostate in males. These organs are actively involved in the involuntary storage of urine formed in the upper urinary tract and the voluntary expulsion of urine at a suitable place and time [7]. The effectiveness of these functions depend on the activity of striated and smooth muscles in the bladder, urethra and external urethral sphincter, which is in turn controlled by neural circuits in the spinal cord, peripheral ganglia and brain [4]. Owning to the differences in sexual function and pelvic anatomy, there are considerable differences in the anatomy of LUT in males

The bladder is a hollow organ located within the pelvis. Its wall consists of five layers from inside out, and the muscle of the bladder, the detrusor, is composed of smooth muscle fibers [9]. The wall thickness of the bladder decreases from 2 cm to 2 mm during expansion. The principal function of the bladder is that of a reservoir, storing urine at lower pressures, even with large filling volumes. The normal bladder holds 200–500 ml urine, and for imaging assessment, a full bladder is preferred for visualization. Due to the visco-elastic properties of the bladder wall and the inhibition of the filling phase detrusor contractions, the bladder is compliant and the pressure inside usually remain low [10]. In the clinical assessment of images of the LUT, it is important to note the close relation between the anterior vaginal wall and the urethra in women and between seminal vesicles and prostate and posterior

The primary physiological functions of the LUT are the storage of urine (at relatively low pressure) and its voiding (expulsion) at appropriate time. LUT dysfunction is a common problem, and the prevalence increases with ageing. The term "dysfunction" indicates an abnormality in the physiology of the lower urinary tract, including urinary sphincter, associated nervous system, bladder neck and detrusor muscle. This may result in failure to store urine, failure to empty or a combination of both [12]. Lower urinary tract symptoms can thus be divided into storage phase symptoms, voiding phase symptoms and postmicturition symptoms. These symptoms can be caused by various types of bladder dysfunctions

**26**

Voiding as intended by nature should result in complete emptying of the bladder. This depends on a coordinated contraction of the detrusor smooth muscle with a simultaneous lowering of bladder outlet resistance. Distortion, compression or occlusion of the outlet of the bladder obstructs urine flow during expulsion, with attendant characteristic symptoms of dribbling, poor stream, incomplete emptying and hesitancy. Bladder outlet obstruction (BOO) is an indication of the existence of abnormal tissue which modifies the configuration of the bladder outlet through distortion, compression or occlusion, thus impeding the urine flow at the time of expulsion. Accompanying urine symptoms include slow stream, intermittent stream, hesitancy, straining to void, terminal dribble, post-micturition dribble and feeling of incomplete emptying [15].

These LUT symptoms are caused by a variety of different pathologies. The commonest processes responsible for BOO in men are benign prostatic enlargement (BPE) or urethral stricture disease [15]. For lesser degrees of obstruction, the symptomatic consequences may be slight, owing to compensatory responses, such as enhanced bladder contractility. However, a potential feature of BPE is the progression of obstruction with ageing, which leads to evident expulsion and post-micturition LUT symptoms. Also, the emergence of LUT symptoms point to relative inadequacy in the expulsive capacity of the bladder, which may be a consequence of detrusor underactivity. Detrusor underactivity is characterized by a contraction of reduced duration and/or strength, thus resulting in failure to achieve complete bladder emptying within regular time span and/or prolonged bladder emptying. The variables of detrusor contraction strength, contraction duration and outlet obstruction severity leads to varied clinical features of BOO. The basis of obstruction in females may be bladder neck distortion, urethral compression or luminal occlusion and functional issues [16]. However, in women, due to difficulty in assessing bladder contractility, there is difficulty in arriving at decisions on issues regarding diagnosis of BOO [15]. Diagnosis of BOO can be made based on invasive urodynamic study, such as videourodynamic study or pressure flow study. Also, a noninvasive method to diagnose BOO is needed for more accurate treatment [17].

#### *2.1.2 Overactive bladder (OAB) and detrusor overactivity (DO)*

According to the International Continence Society (ICS), overactive bladder (OAB) is defined as a complex of urgency, usually with increased daytime frequency and nocturia, with (OAB wet) or without (OAB dry) urinary incontinence. Urgency is the key symptom of OAB, and it is a sudden compelling desire to pass urine, which is difficult to defer [18]. In diagnosing OAB, it is assumed that conflicting issues such as, urinary tract infections are excluded. OAB might be because of increased bladder sensation or detrusor overactivity (DO). Confusion usually exists between these two disease states because patients usually cannot differentiate the sensation of urgency from the urge to void [19].

DO is an urodynamic observation characterized by involuntary detrusor contractions during the filling phase that may be provoked or spontaneous. The ICS 2002 report categorizes DO into two types: (1) terminal, which is a single involuntary detrusor contraction that often results in complete bladder emptying; and (2) phasic, which may or may not lead to urinary incontinence. Therefore, OAB is a symptom-based diagnosis, while DO is an urodynamic diagnosis. A research on OAB and DOO showed that 64% of patients with OAB symptoms had DO on urodynamic investigation, while 30% of the patients with DO did not have AOB [18].

#### **3. Imaging modalities used for the clinical assessment of LUTD**

The lower urinary tract (LUT) requires coordination of the prostate, bladder, pelvic floor, urethra, and specific spinal cord and brain areas. Different imaging modalities can be utilized to visualize these structures and are employed to study its pathophysiology and diagnose voiding dysfunction. Although the bladder and urethra are anatomically distinct structures, they are functionally closely interrelated. Therefore, imaging of the bladder is often needed to confirm clinical examination.

Imaging modalities including ultrasound (US), voiding cystourethrogram X-ray (VCUG), magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are used to visualize the distinctive structures of the LUT. US is the commonly used technique in daily practice, to evaluate LUTD. The utilization of MRI for voiding dysfunction however remains limited, but several clinical studies have already shown its potential in the benign prostatic hyperplasia (BPH) and diagnosis of stress urinary incontinence. Also, PET and fMRI of the brain have made it possible to study supraspinal control of the LUT, in the light of LUT being subjected to a complex neural control mechanism.

Urodynamic tests have over the years been considered the gold standard method for diagnosing common conditions of the lower urinary tract such detrusor overactivity (DO) and bladder outlet obstruction (BOO). However, with increasing concern about their "invasiveness" and associated potential patient morbidity, there has been a search towards non-invasive techniques such as ultrasound, computed tomography (CT), PET, magnetic resonance imaging (MRI), with the potential of becoming the mainstay diagnostic tools for LUTD. Furthermore, clinical assessment of the urethral symptoms is challenging and often requires further evaluation with imaging.

#### **3.1 Ultrasonography**

Ultrasonography (US) has over the years emerged as the most widely used imaging technique for the study of the LUT. In the past, US was identified as a technique of approach and guidance for the evaluation of LUT, but it is now recognized worldwide as the investigation of choice allowing precise diagnosis of many pathological conditions of the LUT, usually obviating the need for further radiological examinations. For instance, Transabdominal US is a cheap and easy modality to evaluate structural abnormalities of the bladder, stone disease of the bladder, postvoid residual urine (PVR) or vesico-ureteral junction, neoplasms and inflammatory disorders [20].

The US, although simple to use, safe and acceptable by majority of patients, still remains real-time operator dependent, and in the light of new applications, requires experienced and skilled operator in whose hands often becomes the only exam needed to be able to direct the next phase of the diagnostic algorithm. Recent advances in US, incorporating a high resolution multi frequency transducers allows a meticulous study of the kidneys, its size, location and parenchymal structure,

**29**

*Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract…*

lesions such as calculi by the non-distended bladder folds [22].

*3.1.1 Ultrasonographic methods in the assessment of LUTD*

intravesical volume assuming a spherical bladder (see **Figure 1**).

The benefit of utilizing US to monitor the deformation in the detrusor muscle have been shown by a recent study [33]. This provides insight into the detrusor muscle's dynamic and structural properties related to bladder pressure. In the study, it was demonstrated that US could be used to estimate strain in the detrusor muscle, which was positively correlated with the detrusor pressure. This suggests a possibility of using US in a real time manner to monitor detrusor muscle activity. Also, this

including a thorough assessment of the urinary bladder, perivesical space as well as pelvicalyceal and ureteral dilatation [21]. The use of US requires when possible a full bladder which is not distended to the extent that the individual has pain. This is necessary because, it is only a well-distended bladder that allows true mass abnormalities to be seen, or else, apparent focal wall diverticula or masses can be stimulated by invaginations of the deflated bladder, usually obscuring true bladder

In the assessment of LUT using US, patients are normally examined in the supine position but sometimes is required when there is the need to differentiate mobile intravesical abnormalities such as foreign bodies or stones from fixed lesions. The use of a 3.5–5-MHz curved array is normally acceptable for most US examinations of the LUT, however, with regards to anterior bladder wall, higher frequency linear probes are sometimes required for better resolution [22].

Ultrasonography has proven to be essential in the evaluation of patients with lower urinary tract dysfunction (LUTD). This is based on the premise that LUTD may result in an alteration of the anatomic structures of the lower urinary tract (LUT) and vice versa [23]. In routine practice, US is mostly used to accurately measure the post-void residual urine (PVR) which indicates how completely an individual empties his bladder. Individuals with bladder outlet obstruction (BOO) and/or detrusor underactivity are commonly associated with elevated PVR [24]. The ultrasound measurement of bladder wall thickness (BWT) has also been linked to the diagnosis of overactive bladder (OAB) and BOO, with several studies reporting that increases in BWT can be a valuable biomarker for detrusor overactivity (DO) in subjects with an OAB syndrome [25, 26]. This is based on the assumption that increased BWT in BOO or OAB is secondary to hypertrophy of the detrusor wall, which is associated with increased isometric detrusor contraction against a competent urethral sphincter. These contractions lead to a rise in intravesical pressure, giving the individual a very strong desire to void [27]. Furthermore, it is generally accepted that an increase in mean BWT is unique to DO, with a study recording a statistically significant correlation between DO and BWT [27]. Detrusor wall thickness (DWT) might be a more accurate measure for BOO. A DWT >2 mm has been reported in 94% of men with signs of BOO on urodynamics [28]. In addition, measurement of DWT or BWT with US can used to examine the response to surgical or medical treatment of BOO. For instance, reduced BWT is detected after treatment with α-1 receptor blockers and transvesical prostatectomy [29, 30]. The ultrasonographic sections of the urinary bladder are defined from outside-in as bladder hyperechoic (adventitia), hypoechoic (detrusor muscle) and hyperechoic (bladder mucosa) [31, 32]. DWT measures only the middle layer, while the measurement of BWT involves all the three layers. The only issue with BWT measurement is that, it is volume dependent, and bladder wall thickness decrease with increasing filling volume. Hence, there is the need to measure bladder weight which should remain constant at different bladder volumes. Thus, with the aid of US, bladder weight is calculated from the thickness of the bladder wall and the

*DOI: http://dx.doi.org/10.5772/intechopen.86934*

#### *Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract… DOI: http://dx.doi.org/10.5772/intechopen.86934*

including a thorough assessment of the urinary bladder, perivesical space as well as pelvicalyceal and ureteral dilatation [21]. The use of US requires when possible a full bladder which is not distended to the extent that the individual has pain. This is necessary because, it is only a well-distended bladder that allows true mass abnormalities to be seen, or else, apparent focal wall diverticula or masses can be stimulated by invaginations of the deflated bladder, usually obscuring true bladder lesions such as calculi by the non-distended bladder folds [22].

In the assessment of LUT using US, patients are normally examined in the supine position but sometimes is required when there is the need to differentiate mobile intravesical abnormalities such as foreign bodies or stones from fixed lesions. The use of a 3.5–5-MHz curved array is normally acceptable for most US examinations of the LUT, however, with regards to anterior bladder wall, higher frequency linear probes are sometimes required for better resolution [22].

#### *3.1.1 Ultrasonographic methods in the assessment of LUTD*

Ultrasonography has proven to be essential in the evaluation of patients with lower urinary tract dysfunction (LUTD). This is based on the premise that LUTD may result in an alteration of the anatomic structures of the lower urinary tract (LUT) and vice versa [23]. In routine practice, US is mostly used to accurately measure the post-void residual urine (PVR) which indicates how completely an individual empties his bladder. Individuals with bladder outlet obstruction (BOO) and/or detrusor underactivity are commonly associated with elevated PVR [24]. The ultrasound measurement of bladder wall thickness (BWT) has also been linked to the diagnosis of overactive bladder (OAB) and BOO, with several studies reporting that increases in BWT can be a valuable biomarker for detrusor overactivity (DO) in subjects with an OAB syndrome [25, 26]. This is based on the assumption that increased BWT in BOO or OAB is secondary to hypertrophy of the detrusor wall, which is associated with increased isometric detrusor contraction against a competent urethral sphincter. These contractions lead to a rise in intravesical pressure, giving the individual a very strong desire to void [27]. Furthermore, it is generally accepted that an increase in mean BWT is unique to DO, with a study recording a statistically significant correlation between DO and BWT [27]. Detrusor wall thickness (DWT) might be a more accurate measure for BOO. A DWT >2 mm has been reported in 94% of men with signs of BOO on urodynamics [28]. In addition, measurement of DWT or BWT with US can used to examine the response to surgical or medical treatment of BOO. For instance, reduced BWT is detected after treatment with α-1 receptor blockers and transvesical prostatectomy [29, 30]. The ultrasonographic sections of the urinary bladder are defined from outside-in as bladder hyperechoic (adventitia), hypoechoic (detrusor muscle) and hyperechoic (bladder mucosa) [31, 32]. DWT measures only the middle layer, while the measurement of BWT involves all the three layers. The only issue with BWT measurement is that, it is volume dependent, and bladder wall thickness decrease with increasing filling volume. Hence, there is the need to measure bladder weight which should remain constant at different bladder volumes. Thus, with the aid of US, bladder weight is calculated from the thickness of the bladder wall and the intravesical volume assuming a spherical bladder (see **Figure 1**).

The benefit of utilizing US to monitor the deformation in the detrusor muscle have been shown by a recent study [33]. This provides insight into the detrusor muscle's dynamic and structural properties related to bladder pressure. In the study, it was demonstrated that US could be used to estimate strain in the detrusor muscle, which was positively correlated with the detrusor pressure. This suggests a possibility of using US in a real time manner to monitor detrusor muscle activity. Also, this

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

a complex neural control mechanism.

with imaging.

disorders [20].

**3.1 Ultrasonography**

2002 report categorizes DO into two types: (1) terminal, which is a single involuntary detrusor contraction that often results in complete bladder emptying; and (2) phasic, which may or may not lead to urinary incontinence. Therefore, OAB is a symptom-based diagnosis, while DO is an urodynamic diagnosis. A research on OAB and DOO showed that 64% of patients with OAB symptoms had DO on urodynamic investigation, while 30% of the patients with DO did not have AOB [18].

**3. Imaging modalities used for the clinical assessment of LUTD**

The lower urinary tract (LUT) requires coordination of the prostate, bladder, pelvic floor, urethra, and specific spinal cord and brain areas. Different imaging modalities can be utilized to visualize these structures and are employed to study its pathophysiology and diagnose voiding dysfunction. Although the bladder and urethra are anatomically distinct structures, they are functionally closely interrelated. Therefore, imaging of the bladder is often needed to confirm clinical examination. Imaging modalities including ultrasound (US), voiding cystourethrogram X-ray (VCUG), magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are used to visualize the distinctive structures of the LUT. US is the commonly used technique in daily practice, to evaluate LUTD. The utilization of MRI for voiding dysfunction however remains limited, but several clinical studies have already shown its potential in the benign prostatic hyperplasia (BPH) and diagnosis of stress urinary incontinence. Also, PET and fMRI of the brain have made it possible to study supraspinal control of the LUT, in the light of LUT being subjected to

Urodynamic tests have over the years been considered the gold standard method for diagnosing common conditions of the lower urinary tract such detrusor overactivity (DO) and bladder outlet obstruction (BOO). However, with increasing concern about their "invasiveness" and associated potential patient morbidity, there has been a search towards non-invasive techniques such as ultrasound, computed tomography (CT), PET, magnetic resonance imaging (MRI), with the potential of becoming the mainstay diagnostic tools for LUTD. Furthermore, clinical assessment of the urethral symptoms is challenging and often requires further evaluation

Ultrasonography (US) has over the years emerged as the most widely used imaging technique for the study of the LUT. In the past, US was identified as a technique of approach and guidance for the evaluation of LUT, but it is now recognized worldwide as the investigation of choice allowing precise diagnosis of many pathological conditions of the LUT, usually obviating the need for further radiological examinations. For instance, Transabdominal US is a cheap and easy modality to evaluate structural abnormalities of the bladder, stone disease of the bladder, postvoid residual urine (PVR) or vesico-ureteral junction, neoplasms and inflammatory

The US, although simple to use, safe and acceptable by majority of patients, still remains real-time operator dependent, and in the light of new applications, requires experienced and skilled operator in whose hands often becomes the only exam needed to be able to direct the next phase of the diagnostic algorithm. Recent advances in US, incorporating a high resolution multi frequency transducers allows a meticulous study of the kidneys, its size, location and parenchymal structure,

**28**

#### **Figure 1.**

*(A) An ultrasound image of the urinary bladder (transverse scan) showing normal bladder wall thickness (BWT) (a, arrow) in a middle-aged woman with irritative lower urinary tract symptoms (LUTS) and normal filling cystometry (FCM); (B) ultrasound image (longitudinal scan) showing increased BWT (b, arrow) in a middle-aged man with irritative LUTS and detrusor overactivity [26].*

finding is important because, it is an indication that US imaging could be used as a non-invasive modality option to replace the pressure flow studies which remain the standard diagnostic urodynamic tests for lower urinary tract symptoms (LUTS).

With recent advances in US imaging of the urethra, imaging of different structural abnormalities such as urethral neoplasms and urethral diverticulae are now possible. The typical symptoms of urethral diverticula are dyspareunia, urethral pain and post-voiding dribbling [34]. In addition, the multiplanar US allows imaging of the size, location, content, and configuration of the diverticulum. Also, in the case of surgical planning, US allows the diverticulum neck can to be evaluated, together with the presence of calculi in sac [20].

#### *3.1.2 Recent innovations in the field of ultrasonography*

The recent years have seen an evolution in the field of ultrasonography, with the introduction of applications which have great importance in the assessment of LUT. These new applications include harmonic imaging, motion-mode, transperineal US and 3D and 4D ultrasound.

**31**

*Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract…*

allow the comprehensive demonstration of complex pathology [21, 35].

VCUG uses a small amount of radiation to make images of an individual's urinary system, and it enables the assessment of the bladder's size and shape and also looks for abnormalities, such as a blockage along the path of the urine [36]. Images from VCUG can also show whether the urine is moving in the right direction. The normal flow of urine is from the kidneys down to the bladder through the ureters. However, in a condition called vesicoureteral (VU) reflux, urine flows backward from the bladder to one or both ureters and sometimes to the kidneys, and it sometimes occurs only at the voiding stage [37]. VU reflux can be detected by VCUG, which also includes taking X-ray images while the bladder is being emptied. This makes VCUG appropriate for diagnosing VU that only occurs while voiding [38]. During VCUG, a patient's bladder is filled with contrast material, followed by an X-ray machine used to send beams of radiation through the abdomen and pelvis, and images are recorded on special film or a computer. These images help physicians see problems in parts of the urinary system, including the bladder, urethra (the tube connecting the bladder with the outside of the body), and the ureters (the tubes connecting the kidneys to the bladder) (LUT), aiding in diagnosing LUTDS [39].

Technological advancement in imaging modalities, allowing cross-sectional imaging of the LUT is essential for further functional and/or morphological evaluation. Primary disorders for MRI of the LUT are bladder tumors and congenital abnormalities, and in addition, MRI is usually employed as a secondary imaging modality, particularly for assessing voiding dysfunction in pediatric urology [40]. MRI can also be used in conjunction with US for imaging of the size, content and position of the urethral diverticulae (see **Figure 2**). With regards to urethral neoplasms, MRI can reveal different characteristics of the different types of the neoplasms (see **Figure 2**). These neoplasms of the urethra appear as more heterogeneous lobulated, deeply infiltrating or exophytic lesions [20]. Urethral hypermobility can also be identified on both MR imaging and US, and it has been linked with

Currently, MRI is the only imaging modality that provides outstanding functional imaging and anatomical information without the use of ionizing radiation.

**3.2 Voiding cystourethrogram X-ray (VCUG) of LUTD**

**3.3 Magnetic resonance imaging in the assessment of LUTD**

stress urinary incontinence in women [42].

Harmonic imaging (HI) is based on the harmonic response generated by the tissue or, when used by the contrast medium, rather than on the reflection of the fundamental frequency of the ultrasound beam. This provides a better definition of the profiles, particularly of the fluid structure systems, such as reduces artifacts; improves the representation of the contrast medium; and dilated collectors. Thus, HI removes low frequency sonic artifact which is usually the result of reverberation artifact and help better define the bladder wall. Motion-mode (M-mode) assists in the assessment of movement, and is therefore valuable in providing documentation and semiquantitative evaluation of ureteral peristalsis. Transperineal US, incorporating high-frequency linear probes allows ideal visualization of the vagina, urethra and surrounding structures. 3D and 4D US offer a multiaxial illustration of the entire kidney and bladder, thus improving renal parenchymal volume calculation, mostly in hydronephrosis or irregularly shaped kidneys. This is possible because, the dilated collecting system can be deducted from the overall kidney volume. Also, the potential of creating rendered views will

*DOI: http://dx.doi.org/10.5772/intechopen.86934*

#### *Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract… DOI: http://dx.doi.org/10.5772/intechopen.86934*

Harmonic imaging (HI) is based on the harmonic response generated by the tissue or, when used by the contrast medium, rather than on the reflection of the fundamental frequency of the ultrasound beam. This provides a better definition of the profiles, particularly of the fluid structure systems, such as reduces artifacts; improves the representation of the contrast medium; and dilated collectors. Thus, HI removes low frequency sonic artifact which is usually the result of reverberation artifact and help better define the bladder wall. Motion-mode (M-mode) assists in the assessment of movement, and is therefore valuable in providing documentation and semiquantitative evaluation of ureteral peristalsis. Transperineal US, incorporating high-frequency linear probes allows ideal visualization of the vagina, urethra and surrounding structures. 3D and 4D US offer a multiaxial illustration of the entire kidney and bladder, thus improving renal parenchymal volume calculation, mostly in hydronephrosis or irregularly shaped kidneys. This is possible because, the dilated collecting system can be deducted from the overall kidney volume. Also, the potential of creating rendered views will allow the comprehensive demonstration of complex pathology [21, 35].

#### **3.2 Voiding cystourethrogram X-ray (VCUG) of LUTD**

VCUG uses a small amount of radiation to make images of an individual's urinary system, and it enables the assessment of the bladder's size and shape and also looks for abnormalities, such as a blockage along the path of the urine [36]. Images from VCUG can also show whether the urine is moving in the right direction. The normal flow of urine is from the kidneys down to the bladder through the ureters. However, in a condition called vesicoureteral (VU) reflux, urine flows backward from the bladder to one or both ureters and sometimes to the kidneys, and it sometimes occurs only at the voiding stage [37]. VU reflux can be detected by VCUG, which also includes taking X-ray images while the bladder is being emptied. This makes VCUG appropriate for diagnosing VU that only occurs while voiding [38].

During VCUG, a patient's bladder is filled with contrast material, followed by an X-ray machine used to send beams of radiation through the abdomen and pelvis, and images are recorded on special film or a computer. These images help physicians see problems in parts of the urinary system, including the bladder, urethra (the tube connecting the bladder with the outside of the body), and the ureters (the tubes connecting the kidneys to the bladder) (LUT), aiding in diagnosing LUTDS [39].

#### **3.3 Magnetic resonance imaging in the assessment of LUTD**

Technological advancement in imaging modalities, allowing cross-sectional imaging of the LUT is essential for further functional and/or morphological evaluation. Primary disorders for MRI of the LUT are bladder tumors and congenital abnormalities, and in addition, MRI is usually employed as a secondary imaging modality, particularly for assessing voiding dysfunction in pediatric urology [40]. MRI can also be used in conjunction with US for imaging of the size, content and position of the urethral diverticulae (see **Figure 2**). With regards to urethral neoplasms, MRI can reveal different characteristics of the different types of the neoplasms (see **Figure 2**). These neoplasms of the urethra appear as more heterogeneous lobulated, deeply infiltrating or exophytic lesions [20]. Urethral hypermobility can also be identified on both MR imaging and US, and it has been linked with stress urinary incontinence in women [42].

Currently, MRI is the only imaging modality that provides outstanding functional imaging and anatomical information without the use of ionizing radiation.

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

finding is important because, it is an indication that US imaging could be used as a non-invasive modality option to replace the pressure flow studies which remain the standard diagnostic urodynamic tests for lower urinary tract symptoms (LUTS). With recent advances in US imaging of the urethra, imaging of different structural abnormalities such as urethral neoplasms and urethral diverticulae are now possible. The typical symptoms of urethral diverticula are dyspareunia, urethral pain and post-voiding dribbling [34]. In addition, the multiplanar US allows imaging of the size, location, content, and configuration of the diverticulum. Also, in the case of surgical planning, US allows the diverticulum neck can to be evaluated,

*(A) An ultrasound image of the urinary bladder (transverse scan) showing normal bladder wall thickness (BWT) (a, arrow) in a middle-aged woman with irritative lower urinary tract symptoms (LUTS) and normal filling cystometry (FCM); (B) ultrasound image (longitudinal scan) showing increased BWT (b,* 

*arrow) in a middle-aged man with irritative LUTS and detrusor overactivity [26].*

The recent years have seen an evolution in the field of ultrasonography, with the introduction of applications which have great importance in the assessment of LUT. These new applications include harmonic imaging, motion-mode, transperi-

together with the presence of calculi in sac [20].

neal US and 3D and 4D ultrasound.

*3.1.2 Recent innovations in the field of ultrasonography*

**30**

**Figure 1.**

#### **Figure 2.**

*A woman undergoing MRI evaluation of possible urethral diverticulum. Patient had previously undergone hysterectomy. Midline sagittal T2-weighted TSE image (6000/116, flip angle, 180°) obtained at rest shows no significant prolapse. Solid line represents pubococcygeal line, above which all pelvic organs are located. B = bladder, dotted line = urethra, R = rectum. Adapted from Bennett et al. [41].*

MR imaging, in the light of rapid technological changes is now faster with less movement artifact, and therefore improved image quality and resolution. It allows an overall evaluation of the renal parenchyma, excretory cavity, surrounding tissue, together with the main vessels. The dynamic contrast enhancement of MRI is comparable to renal scintigraphy, and thus ensures a higher contrast spatial and temporal resolution. As a result of this inherently superior contrast resolution, MRI of the pelvis provides much better anatomical visualization than CT. Furthermore, heavy T2-weighted MRI is well suited for imaging of the urinary bladder, since the organ is filled with fluid, thus improving bladder visualization. With the advent of diffusion weighted MRI, in which imaging and MRI signals are weighted toward the diffusion characteristics of water, evaluation of LUT neoplasms, particularly bladder cancer has been done [21].

The evident advantages of MRI include the lack of both nephrotoxic contrast media and ionizing radiation required for CT, thus making it particularly suitable for imaging during renal failure and pregnancy. As a result, indications for MRI have been increasing rapidly over the years, and it is currently used as the standard imaging modality for staging pelvic cancers. In fact, it is better than CT for the anatomical depiction of the bladder wall [22].

#### **3.4 Computed tomography in the assessment of LUTD**

The combination of contrast studies and US scan have revolutionized imaging of LUT, pinpointing many of the clinical problems originating in the bladder. CT has become a vital complementary tool in the investigation of several disorders, and crucial for staging cancers. Thus, CT imaging is often employed in the staging of bladder cancer, however, its utility in the evaluation of LUTD remains limited. CT is the standard imaging modality for the study of adult urology, with or without contrast medium for the detection of stones [22]. Key advantages of CT are in providing detailed demonstration of overall bladder and pelvic anatomy.

Considering the fact that CT examination is highly radiant, its diagnostic potential cannot be transferred carelessly to children, since they have a higher radio

**33**

*Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract…*

sensitivity, smaller structures, lesser representation of adipose tissue, different tissue composition and different diseases, contrary to that of adults. Also, CT is not suitable for imaging of the urethra, penis and prostate, which are better assessed with MRI. That is, CT has limitations when applied to the urinary tract beyond the

Nevertheless, recent technological advancement in CT, incorporating multislice scanning with the possibility of isotropic imaging have further enhanced the precision of CT. In isotropic imaging, the block (or voxel) of imaging is acquired as a perfect cube, and is thus as dimensionally accurate as possible. Therefore, the 3D reconstruction of the contrast-filled bladder is rendered precisely, and virtual cystoscopy is possible. Thus, CT urography is being touted as one-stop imaging of the entire urinary tract, with the potential to replace conventional contrast studies

and ultrasound, but this however requires further technical developments.

able to detect rapid changes in brain metabolism [42, 43].

a depth of 1 cm beneath the skull [44].

**assessment of BOO and DO**

cases, other investigations are required.

**3.5 Positron emission tomography and functional MRI in the assessment of** 

Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are powerful non-invasive tools utilized in the study of the supraspinal control of the LUT directly through imaging of the brain. fMRI measures the changing proportion of deoxygenated and oxygenated hemoglobin in activated brain centers, while PET needs the injection of a radioactive isotope that will accumulate in a metabolically active brain region [20]. fMRI has a superb spatial and temporal resolution but needs multiple runs of the same event to increase signal-tonoise ratio, while PET is very sensitive for small changes in neural activity but not

Near infrared spectroscopy (NIRS) is occasionally utilized in the study of supraspinal control of the bladder. NIRS takes advantage of the varying concentrations of hemoglobin in the cerebral cortex, but its key disadvantage is the very limited resolution for deeper brain structures since it can only accurately measure to

In recent years, these different brain imaging techniques have been widely spread and optimized, providing a vast amount of literature about nearly every human cortical function. Unfortunately, the number of studies that have looked into brain control of bladder function is until now still relatively small, but nevertheless these studies have provided us with valuable new insights into LUT

**3.6 Imaging modalities as surrogates to urodynamic tests for the clinical** 

interpreted results, coupled with associated potential patient morbidity.

Therefore, the search for non-invasive diagnostic tests as potential replacement for these urodynamic tests, especially for the diagnosis of BOO, has been

Lower urinary tract symptoms alone are usually not sufficient in diagnosing common complications of the LUT such as BOO, DO and BPE. Hence, in most

Uroflowmetry, though cheaper and easy to perform in clinical setting, is limited by its lack of specificity and inability to differentiate between BOO and detrusor underactivity. In much the same way, pressure-flow studies which serve as gold standard for diagnosing BOO are able to provide key information on the presence of obstruction as well as detrusor contractility. But this come at a cost, as urodynamic tests are invasive and require specialist equipment and training to perform tests and

*DOI: http://dx.doi.org/10.5772/intechopen.86934*

bladder.

**LUTD**

pathophysiology.

#### *Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract… DOI: http://dx.doi.org/10.5772/intechopen.86934*

sensitivity, smaller structures, lesser representation of adipose tissue, different tissue composition and different diseases, contrary to that of adults. Also, CT is not suitable for imaging of the urethra, penis and prostate, which are better assessed with MRI. That is, CT has limitations when applied to the urinary tract beyond the bladder.

Nevertheless, recent technological advancement in CT, incorporating multislice scanning with the possibility of isotropic imaging have further enhanced the precision of CT. In isotropic imaging, the block (or voxel) of imaging is acquired as a perfect cube, and is thus as dimensionally accurate as possible. Therefore, the 3D reconstruction of the contrast-filled bladder is rendered precisely, and virtual cystoscopy is possible. Thus, CT urography is being touted as one-stop imaging of the entire urinary tract, with the potential to replace conventional contrast studies and ultrasound, but this however requires further technical developments.

#### **3.5 Positron emission tomography and functional MRI in the assessment of LUTD**

Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are powerful non-invasive tools utilized in the study of the supraspinal control of the LUT directly through imaging of the brain. fMRI measures the changing proportion of deoxygenated and oxygenated hemoglobin in activated brain centers, while PET needs the injection of a radioactive isotope that will accumulate in a metabolically active brain region [20]. fMRI has a superb spatial and temporal resolution but needs multiple runs of the same event to increase signal-tonoise ratio, while PET is very sensitive for small changes in neural activity but not able to detect rapid changes in brain metabolism [42, 43].

Near infrared spectroscopy (NIRS) is occasionally utilized in the study of supraspinal control of the bladder. NIRS takes advantage of the varying concentrations of hemoglobin in the cerebral cortex, but its key disadvantage is the very limited resolution for deeper brain structures since it can only accurately measure to a depth of 1 cm beneath the skull [44].

In recent years, these different brain imaging techniques have been widely spread and optimized, providing a vast amount of literature about nearly every human cortical function. Unfortunately, the number of studies that have looked into brain control of bladder function is until now still relatively small, but nevertheless these studies have provided us with valuable new insights into LUT pathophysiology.

#### **3.6 Imaging modalities as surrogates to urodynamic tests for the clinical assessment of BOO and DO**

Lower urinary tract symptoms alone are usually not sufficient in diagnosing common complications of the LUT such as BOO, DO and BPE. Hence, in most cases, other investigations are required.

Uroflowmetry, though cheaper and easy to perform in clinical setting, is limited by its lack of specificity and inability to differentiate between BOO and detrusor underactivity. In much the same way, pressure-flow studies which serve as gold standard for diagnosing BOO are able to provide key information on the presence of obstruction as well as detrusor contractility. But this come at a cost, as urodynamic tests are invasive and require specialist equipment and training to perform tests and interpreted results, coupled with associated potential patient morbidity.

Therefore, the search for non-invasive diagnostic tests as potential replacement for these urodynamic tests, especially for the diagnosis of BOO, has been

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

MR imaging, in the light of rapid technological changes is now faster with less movement artifact, and therefore improved image quality and resolution. It allows an overall evaluation of the renal parenchyma, excretory cavity, surrounding tissue, together with the main vessels. The dynamic contrast enhancement of MRI is comparable to renal scintigraphy, and thus ensures a higher contrast spatial and temporal resolution. As a result of this inherently superior contrast resolution, MRI of the pelvis provides much better anatomical visualization than CT. Furthermore, heavy T2-weighted MRI is well suited for imaging of the urinary bladder, since the organ is filled with fluid, thus improving bladder visualization. With the advent of diffusion weighted MRI, in which imaging and MRI signals are weighted toward the diffusion characteristics of water, evaluation of LUT neoplasms, particularly

*B = bladder, dotted line = urethra, R = rectum. Adapted from Bennett et al. [41].*

*A woman undergoing MRI evaluation of possible urethral diverticulum. Patient had previously undergone hysterectomy. Midline sagittal T2-weighted TSE image (6000/116, flip angle, 180°) obtained at rest shows no significant prolapse. Solid line represents pubococcygeal line, above which all pelvic organs are located.* 

The evident advantages of MRI include the lack of both nephrotoxic contrast media and ionizing radiation required for CT, thus making it particularly suitable for imaging during renal failure and pregnancy. As a result, indications for MRI have been increasing rapidly over the years, and it is currently used as the standard imaging modality for staging pelvic cancers. In fact, it is better than CT for the

The combination of contrast studies and US scan have revolutionized imaging of LUT, pinpointing many of the clinical problems originating in the bladder. CT has become a vital complementary tool in the investigation of several disorders, and crucial for staging cancers. Thus, CT imaging is often employed in the staging of bladder cancer, however, its utility in the evaluation of LUTD remains limited. CT is the standard imaging modality for the study of adult urology, with or without contrast medium for the detection of stones [22]. Key advantages of CT are in providing detailed demonstration of overall bladder and pelvic anatomy.

Considering the fact that CT examination is highly radiant, its diagnostic potential cannot be transferred carelessly to children, since they have a higher radio

bladder cancer has been done [21].

**Figure 2.**

anatomical depiction of the bladder wall [22].

**3.4 Computed tomography in the assessment of LUTD**

**32**

ongoing for many years. As such, parameters such as PVR, free uroflowmetry and quantification of prostate volume has been investigated. However, over the past two decades, the interest has been on BWT, DWT and bladder wall weight, owing to the rationale that BOO and DO are associated with an increase in bladder wall thickness and detrusor hypertrophy. These parameters (BWT, DWT) has been shown by several studies to be diagnostic of BOO and DO. Ultrasonography has thus emerged as the easiest and non-invasive option capable of measuring BWT, DWT and bladder wall weight, thus potentially obviating the need to resort to cumbersome and invasive urodynamic tests to diagnose BOO and DO (see **Figure 1**).

### **4. Conclusion**

Imaging techniques can contribute prominently to our current understanding of lower urinary tract dysfunction. A variety of imaging modalities is available to visualize the urethra, bladder, prostate and pelvic floor. These techniques can be used to enhance our current knowledge of LUT pathophysiology and confirm clinical diagnosis, as an alternative diagnostic method to replace invasive urodynamic studies.

### **Acknowledgements**

We acknowledge the entire staff of Spectra Health Imaging and Interventional Radiology for their valuable support during the preparation of this work.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

George Asafu Adjaye Frimpong1,2\*, Evans Aboagye2,3 and Akosua Asafu-Adjaye Frimpong2

1 Department of Radiology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

2 Spectra Health Imaging and Interventional Radiology, Kumasi, Ghana

3 Department of Molecular Medicine, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

\*Address all correspondence to: george.frimpong@spectrahealthgh.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**35**

*Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract…*

[9] De Groat WC. Anatomy and physiology of the lower urinary tract. The Urologic Clinics of North America.

[10] Coyne KS, Sexton CC, Vats V, Thompson C, Kopp ZS, Milsom I. National community prevalence of overactive bladder in the United States stratified by sex and age. Urology. 2011;**77**(5):1081-1087. DOI: 10.1016/j.

1993;**20**(3):383

urology.2010.08.039

pp. 154-158

[11] Dorph S. Imaging of the lower urinary tract. In: Chest, Musculoskeleton, GI and Abdomen, Urinary Tract. Milano: Springer; 1996.

[12] Wein AJ. Classification of neurogenic voiding dysfunction.

1981;**125**(5):605-609. DOI: 10.1016/

[13] Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourology and Urodynamics. 2002;**21**(2):167-178. DOI:

[14] Sexton CC, Coyne KS, Kopp ZS, Irwin DE, Milsom I, Aiyer LP, et al. The overlap of storage, voiding and postmicturition symptoms and

implications for treatment seeking in the USA, UK and Sweden: EpiLUTS. BJU International. 2009;**103**:12-23. DOI: 10.1111/j.1464-410X.2009.08369.x

[15] Wein AJ, Andersson KE, Drake MJ, Dmochowski RR. Bladder Dysfunction in the Adult: The Basis for Clinical Management. New York: Springer; 2014. DOI: 10. 1007/978-1-4939-0853-0

[16] Goldman HB, Zimmern PE. The treatment of female bladder outlet

The Journal of Urology.

S0022-5347(17)55134-4

10.1002/nau.10052

*DOI: http://dx.doi.org/10.5772/intechopen.86934*

[1] Morrison J, Birder L, Craggs M, De Groat WC, Downie J, Drake M, et al. Neural control. In: Abrams P, Cardozo L, Khoury S, Wein A, editors.

Publications, Ltd; 2005. pp. 363-422

[2] Fry CH, Brading AF, Hussain M, Lewis SA, Takeda M, Tuttle JB, et al. Cell biology. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. Jersey: Health Publications, Ltd; 2005.

[3] De Groat WC. Integrative control of the lower urinary tract: Preclinical perspective. British Journal of

Pharmacology. 2006;**147**(S2):S25-S40.

[5] National Clinical Guideline Centre. Urinary incontinence in neurological disease: Management of lower urinary tract dysfunction in neurological

[6] Panicker JN, Fowler CJ, Kessler TM. Lower urinary tract dysfunction in the neurological patient: Clinical assessment and management. The Lancet Neurology. 2015;**14**(7):720-732. DOI: 10.1016/S1474-4422(15)00070-8

[7] Patel AK, Chapple CR. Anatomy of the lower urinary tract. Surgery (Oxford). 2008;**26**(4):127-132. DOI: https://doi.org/10.1016/j.

[8] Klingler HC, Madersbacher S, Djavan B, Schatzl G, Marberger M, Schmidbauer CP. Morbidity of the evaluation of the lower urinary tract with transurethral multichannel pressure-flow studies. The Journal of Urology. 1998;**159**(1):191-194. DOI: 10.1016/S0022-5347(01)64054-0

mpsur.2008.03.011

DOI: 10.1038/sj.bjp.0706604

[4] De Groat WC, Yoshimura N. Pharmacology of the lower urinary tract. Annual Review of Pharmacology and Toxicology. 2001;**41**(1):691-721

Incontinence. Jersey: Health

**References**

pp. 313-362

disease

*Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract… DOI: http://dx.doi.org/10.5772/intechopen.86934*

#### **References**

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

invasive urodynamic tests to diagnose BOO and DO (see **Figure 1**).

**4. Conclusion**

**Acknowledgements**

**Conflict of interest**

**Author details**

The authors declare no conflict of interest.

George Asafu Adjaye Frimpong1,2\*, Evans Aboagye2,3

and Akosua Asafu-Adjaye Frimpong2

Technology, Kumasi, Ghana

Technology, Kumasi, Ghana

provided the original work is properly cited.

ongoing for many years. As such, parameters such as PVR, free uroflowmetry and quantification of prostate volume has been investigated. However, over the past two decades, the interest has been on BWT, DWT and bladder wall weight, owing to the rationale that BOO and DO are associated with an increase in bladder wall thickness and detrusor hypertrophy. These parameters (BWT, DWT) has been shown by several studies to be diagnostic of BOO and DO. Ultrasonography has thus emerged as the easiest and non-invasive option capable of measuring BWT, DWT and bladder wall weight, thus potentially obviating the need to resort to cumbersome and

Imaging techniques can contribute prominently to our current understanding of lower urinary tract dysfunction. A variety of imaging modalities is available to visualize the urethra, bladder, prostate and pelvic floor. These techniques can be used to enhance our current knowledge of LUT pathophysiology and confirm clinical diagnosis, as an alternative diagnostic method to replace invasive urodynamic studies.

We acknowledge the entire staff of Spectra Health Imaging and Interventional

Radiology for their valuable support during the preparation of this work.

1 Department of Radiology, Kwame Nkrumah University of Science and

2 Spectra Health Imaging and Interventional Radiology, Kumasi, Ghana

\*Address all correspondence to: george.frimpong@spectrahealthgh.com

3 Department of Molecular Medicine, Kwame Nkrumah University of Science and

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

**34**

[1] Morrison J, Birder L, Craggs M, De Groat WC, Downie J, Drake M, et al. Neural control. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. Jersey: Health Publications, Ltd; 2005. pp. 363-422

[2] Fry CH, Brading AF, Hussain M, Lewis SA, Takeda M, Tuttle JB, et al. Cell biology. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. Jersey: Health Publications, Ltd; 2005. pp. 313-362

[3] De Groat WC. Integrative control of the lower urinary tract: Preclinical perspective. British Journal of Pharmacology. 2006;**147**(S2):S25-S40. DOI: 10.1038/sj.bjp.0706604

[4] De Groat WC, Yoshimura N. Pharmacology of the lower urinary tract. Annual Review of Pharmacology and Toxicology. 2001;**41**(1):691-721

[5] National Clinical Guideline Centre. Urinary incontinence in neurological disease: Management of lower urinary tract dysfunction in neurological disease

[6] Panicker JN, Fowler CJ, Kessler TM. Lower urinary tract dysfunction in the neurological patient: Clinical assessment and management. The Lancet Neurology. 2015;**14**(7):720-732. DOI: 10.1016/S1474-4422(15)00070-8

[7] Patel AK, Chapple CR. Anatomy of the lower urinary tract. Surgery (Oxford). 2008;**26**(4):127-132. DOI: https://doi.org/10.1016/j. mpsur.2008.03.011

[8] Klingler HC, Madersbacher S, Djavan B, Schatzl G, Marberger M, Schmidbauer CP. Morbidity of the evaluation of the lower urinary tract with transurethral multichannel pressure-flow studies. The Journal of Urology. 1998;**159**(1):191-194. DOI: 10.1016/S0022-5347(01)64054-0

[9] De Groat WC. Anatomy and physiology of the lower urinary tract. The Urologic Clinics of North America. 1993;**20**(3):383

[10] Coyne KS, Sexton CC, Vats V, Thompson C, Kopp ZS, Milsom I. National community prevalence of overactive bladder in the United States stratified by sex and age. Urology. 2011;**77**(5):1081-1087. DOI: 10.1016/j. urology.2010.08.039

[11] Dorph S. Imaging of the lower urinary tract. In: Chest, Musculoskeleton, GI and Abdomen, Urinary Tract. Milano: Springer; 1996. pp. 154-158

[12] Wein AJ. Classification of neurogenic voiding dysfunction. The Journal of Urology. 1981;**125**(5):605-609. DOI: 10.1016/ S0022-5347(17)55134-4

[13] Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourology and Urodynamics. 2002;**21**(2):167-178. DOI: 10.1002/nau.10052

[14] Sexton CC, Coyne KS, Kopp ZS, Irwin DE, Milsom I, Aiyer LP, et al. The overlap of storage, voiding and postmicturition symptoms and implications for treatment seeking in the USA, UK and Sweden: EpiLUTS. BJU International. 2009;**103**:12-23. DOI: 10.1111/j.1464-410X.2009.08369.x

[15] Wein AJ, Andersson KE, Drake MJ, Dmochowski RR. Bladder Dysfunction in the Adult: The Basis for Clinical Management. New York: Springer; 2014. DOI: 10. 1007/978-1-4939-0853-0

[16] Goldman HB, Zimmern PE. The treatment of female bladder outlet

obstruction. BJU International. 2006;**98**(2):359-366. DOI: 10.1111/j.1464-410X.2006.06335.x

[17] Ke QS, Kuo HC. The promise of bladder wall thickness as a useful biomarker for objective diagnosis of lower urinary tract dysfunction. Tzu Chi Medical Journal. 2011;**23**(1):1-8. DOI: 10.1016/j.tcmj.2011.03.005

[18] Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology in lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Urology. 2003;**61**(1, 1):37-49. DOI: 10.1016/ S0090-4295(02)02243-4

[19] Hashim H, Abrams P. Is the bladder a reliable witness for predicting detrusor overactivity? The Journal of Urology. 2006;**175**(1):191-194. DOI: 10.1016/ S0022-5347(05)00067-4

[20] Deruyver Y, Hakim L, Franken J, De Ridder D. The use of imaging techniques in understanding lower urinary tract (dys) function. Autonomic Neuroscience. 2016;**200**:11-20. DOI: 10.1016/j. autneu.2016.05.008

[21] Taghizadeh A. Pediatric urology. In: Lima M, Manzoni G, editors. Contemporary Strategies from Fetal Life to Adolescence. Mailand: Springer-Verlag; 2015. DOI: 10.1007/978-88-470-5693-0

[22] Patel U, Rickards D. Imaging and Urodynamics of the Lower Urinary Tract. London: Springer; 2010. DOI: 10.1007/978-1-84882-836-0

[23] Yang JM, Huang WC. Bladder wall thickness on ultrasonographic cystourethrography. Journal of Ultrasound in Medicine. 2003;**22**(8):777-782. DOI: 10.7863/ jum.2003.22.8.777

[24] Abrams PH, Griffiths DJ. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. British Journal of Urology. 1979;**51**(2):129-134. DOI: /10.1111/j.1464-410X.1979.tb02846.x

[25] Khullar V, Cardozo LD, Salvatore S, Hill S. Ultrasound: A noninvasive screening test for detrusor instability. BJOG : An International Journal of Obstetrics and Gynaecology. 1996;**103**(9):904-908. DOI: 10.1111/ j.1471-0528.1996.tb09910.x

[26] Cruz F, Heesakkers J, Khullar V, Tubaro A. Bladder wall thickness in overactive bladder: Does it have a role? European Urology Supplements. 2009;**8**(9):769-771. DOI: 10.1016/j. eursup.2009.05.002

[27] Ali MM, Ahmed AF, Khaled SM, Abozeid H, AbdelMagid ME. Accuracy of ultrasound-measured bladder wall thickness for the diagnosis of detrusor overactivity. The African Journal of Urology. 2015;**21**(1):25-29. DOI: 10.1016/j.afju.2014.11.005

[28] Oelke M, Höfner K, Jonas U, Ubbink D, de la Rosette J, Wijkstra H. Ultrasound measurement of detrusor wall thickness in healthy adults. Neurourology and Urodynamics: Official Journal of the International Continence Society. 2006; **25**(4):308-317. DOI: 10.1002/nau.20242

[29] Tubaro A, Carter S, Hind A, Vicentini C, Miano L. A prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. The Journal of Urology. 2001;**166**(1):172-176. DOI: 10.1016/ S0022-5347(05)66102-2

[30] Egilmez T, Pourbagher MA, Guvel S, Kilinc F, Turunc T, Ozkardes H. Effects of selective alpha-1-adrenergic receptor blockers on bladder weight. Urologia Internationalis. 2006;**76**(1):42-50. DOI: 10.1159/000089734

**37**

ndt/16.1.4

*Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract…*

[38] Nakamura M, Shinozaki T, Taniguchi N, Koibuchi H, Momoi M,

Itoh K. Simultaneous voiding cystourethrography and voiding urosonography reveals utility of

j.1651-2227.2003.tb00826.x

sonographic diagnosis of vesicoureteral reflux in children. Acta Paediatrica. 2003;**92**(12):1422-1426. DOI: 10.1111/

[39] Darge K, Higgins M, Hwang TJ, Delgado J, Shukla A, Bellah R. Magnetic resonance and computed tomography in pediatric urology: An imaging overview for current and future daily practice. Radiologic Clinics. 2013;**51**(4):583-598.

DOI: 10.1016/j.rcl.2013.03.004

[40] Macura KJ, Genadry RR,

Spectrum of abnormalities. Radiographics. 2006;**26**:1135-1149

[41] Bennett GL, Hecht EM,

Bluemke DA. MR imaging of the female urethra and supporting ligaments in assessment of urinary incontinence:

Tanpitukpongse TP, Babb JS, Taouli B, Wong S, et al. MRI of the urethra in women with lower urinary tract

symptoms: Spectrum of findings at static and dynamic imaging. American Journal of Roentgenology. 2009;**193**(6):1708- 1715. DOI: 10.2214/AJR.08.1547

[42] Catana C, Drzezga A, Heiss WD, Rosen BR. PET/MRI for neurologic applications. Journal of Nuclear Medicine. 2012;**53**(12):1916-1925. DOI:

10.2967/jnumed.112.105346

[43] Mier W, Mier D. Advantages in functional imaging of the brain. Frontiers in Human Neuroscience. 2015;**9**:249. DOI: 10.3389/fnhum.2015.00249

[44] Matsumoto S, Ishikawa A,

Matsumoto S, Homma Y. Brain response provoked by different bladder volumes: A near infrared spectroscopy study. Neurourology and Urodynamics. 2011; **30**(4):529-535. DOI: 10.1002/nau.21016

*DOI: http://dx.doi.org/10.5772/intechopen.86934*

[31] Jequier S, Rousseau O. Sonographic measurements of the normal bladder wall in children. American Journal of Roentgenology. 1987;**149**(3):563-566.

[32] Kojima M, Inui E, Ochiai A, Naya Y, Ukimura O, Watanabe H. Ultrasonic estimation of bladder weight as a measure of bladder hypertrophy in men with infravesical obstruction: A preliminary report. Urology. 1996;**47**(6):942-947. DOI: 10.1016/

[33] Idzenga T, Farag F, Heesakkers J, Feitz W, de Korte CL. Noninvasive 2-dimensional monitoring of strain in the detrusor muscle in patients with lower urinary tract symptoms using ultrasound strain imaging. The Journal of Urology. 2013;**189**(4):1402-1408. DOI: 10.1016/j.juro.2012.09.165

DOI: 10.2214/ajr.149.3.563

S0090-4295(96)00059-3

[34] Romanzi LJ, Groutz A,

Blaivas JG. Urethral diverticulum in women: Diverse presentations resulting in diagnostic delay and mismanagement. The Journal of Urology. 2000;**164**(2):428-433. DOI: 10.1016/S0022-5347(05)67377-6

[35] Riccabona M. Pediatric threedimensional ultrasound: Basics and potential clinical value. Clinical

[36] Ključevšek D, Battelino N, Tomažič M, Kersnik Levart T. A comparison of echo-enhanced voiding urosonography with X-ray voiding cystourethrography in the first year of life. Acta Paediatrica. 2012;**101**(5):e235-e239. DOI: 10.1111/j.1651-2227.2011.02588.x

[37] Kenda RB. Imaging techniques for the detection of vesicoureteric reflux: What and when? Nephrology,

Dialysis, Transplantation. 2001;**16**(1):4-7. DOI: 10.1093/

clinimag.2004.08.003

Imaging. 2005;**29**(1):1-5. DOI: 10.1016/j.

*Diagnostic Potential of Imaging Modalities in the Assessment of Lower Urinary Tract… DOI: http://dx.doi.org/10.5772/intechopen.86934*

[31] Jequier S, Rousseau O. Sonographic measurements of the normal bladder wall in children. American Journal of Roentgenology. 1987;**149**(3):563-566. DOI: 10.2214/ajr.149.3.563

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

[24] Abrams PH, Griffiths DJ. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. British Journal of Urology. 1979;**51**(2):129-134. DOI: /10.1111/j.1464-410X.1979.tb02846.x

[25] Khullar V, Cardozo LD, Salvatore S, Hill S. Ultrasound: A noninvasive screening test for detrusor instability. BJOG : An International Journal of Obstetrics and Gynaecology. 1996;**103**(9):904-908. DOI: 10.1111/

j.1471-0528.1996.tb09910.x

eursup.2009.05.002

10.1016/j.afju.2014.11.005

[26] Cruz F, Heesakkers J, Khullar V, Tubaro A. Bladder wall thickness in overactive bladder: Does it have a role? European Urology Supplements. 2009;**8**(9):769-771. DOI: 10.1016/j.

[27] Ali MM, Ahmed AF, Khaled SM, Abozeid H, AbdelMagid ME. Accuracy of ultrasound-measured bladder wall thickness for the diagnosis of detrusor overactivity. The African Journal of Urology. 2015;**21**(1):25-29. DOI:

[28] Oelke M, Höfner K, Jonas U, Ubbink D, de la Rosette J, Wijkstra H. Ultrasound measurement of detrusor wall thickness in healthy adults. Neurourology and Urodynamics: Official Journal of the International Continence Society. 2006; **25**(4):308-317. DOI: 10.1002/nau.20242

[29] Tubaro A, Carter S, Hind A, Vicentini C, Miano L. A prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. The Journal of Urology. 2001;**166**(1):172-176. DOI: 10.1016/

[30] Egilmez T, Pourbagher MA, Guvel S, Kilinc F, Turunc T, Ozkardes H. Effects of selective alpha-1-adrenergic receptor blockers on bladder weight. Urologia Internationalis. 2006;**76**(1):42-50. DOI:

S0022-5347(05)66102-2

10.1159/000089734

obstruction. BJU International. 2006;**98**(2):359-366. DOI:

10.1111/j.1464-410X.2006.06335.x

[17] Ke QS, Kuo HC. The promise of bladder wall thickness as a useful biomarker for objective diagnosis of lower urinary tract dysfunction. Tzu Chi Medical Journal. 2011;**23**(1):1-8. DOI:

10.1016/j.tcmj.2011.03.005

S0090-4295(02)02243-4

S0022-5347(05)00067-4

[20] Deruyver Y, Hakim L,

Autonomic Neuroscience. 2016;**200**:11-20. DOI: 10.1016/j.

autneu.2016.05.008

Franken J, De Ridder D. The use of imaging techniques in understanding lower urinary tract (dys) function.

[21] Taghizadeh A. Pediatric urology. In: Lima M, Manzoni G, editors. Contemporary Strategies from Fetal Life to Adolescence. Mailand: Springer-Verlag; 2015. DOI: 10.1007/978-88-470-5693-0

[22] Patel U, Rickards D. Imaging and Urodynamics of the Lower Urinary Tract. London: Springer; 2010. DOI:

10.1007/978-1-84882-836-0

jum.2003.22.8.777

[23] Yang JM, Huang WC. Bladder wall thickness on ultrasonographic cystourethrography. Journal of Ultrasound in Medicine. 2003;**22**(8):777-782. DOI: 10.7863/

[19] Hashim H, Abrams P. Is the bladder a reliable witness for predicting detrusor overactivity? The Journal of Urology. 2006;**175**(1):191-194. DOI: 10.1016/

[18] Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology in lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Urology. 2003;**61**(1, 1):37-49. DOI: 10.1016/

**36**

[32] Kojima M, Inui E, Ochiai A, Naya Y, Ukimura O, Watanabe H. Ultrasonic estimation of bladder weight as a measure of bladder hypertrophy in men with infravesical obstruction: A preliminary report. Urology. 1996;**47**(6):942-947. DOI: 10.1016/ S0090-4295(96)00059-3

[33] Idzenga T, Farag F, Heesakkers J, Feitz W, de Korte CL. Noninvasive 2-dimensional monitoring of strain in the detrusor muscle in patients with lower urinary tract symptoms using ultrasound strain imaging. The Journal of Urology. 2013;**189**(4):1402-1408. DOI: 10.1016/j.juro.2012.09.165

[34] Romanzi LJ, Groutz A, Blaivas JG. Urethral diverticulum in women: Diverse presentations resulting in diagnostic delay and mismanagement. The Journal of Urology. 2000;**164**(2):428-433. DOI: 10.1016/S0022-5347(05)67377-6

[35] Riccabona M. Pediatric threedimensional ultrasound: Basics and potential clinical value. Clinical Imaging. 2005;**29**(1):1-5. DOI: 10.1016/j. clinimag.2004.08.003

[36] Ključevšek D, Battelino N, Tomažič M, Kersnik Levart T. A comparison of echo-enhanced voiding urosonography with X-ray voiding cystourethrography in the first year of life. Acta Paediatrica. 2012;**101**(5):e235-e239. DOI: 10.1111/j.1651-2227.2011.02588.x

[37] Kenda RB. Imaging techniques for the detection of vesicoureteric reflux: What and when? Nephrology, Dialysis, Transplantation. 2001;**16**(1):4-7. DOI: 10.1093/ ndt/16.1.4

[38] Nakamura M, Shinozaki T, Taniguchi N, Koibuchi H, Momoi M, Itoh K. Simultaneous voiding cystourethrography and voiding urosonography reveals utility of sonographic diagnosis of vesicoureteral reflux in children. Acta Paediatrica. 2003;**92**(12):1422-1426. DOI: 10.1111/ j.1651-2227.2003.tb00826.x

[39] Darge K, Higgins M, Hwang TJ, Delgado J, Shukla A, Bellah R. Magnetic resonance and computed tomography in pediatric urology: An imaging overview for current and future daily practice. Radiologic Clinics. 2013;**51**(4):583-598. DOI: 10.1016/j.rcl.2013.03.004

[40] Macura KJ, Genadry RR, Bluemke DA. MR imaging of the female urethra and supporting ligaments in assessment of urinary incontinence: Spectrum of abnormalities. Radiographics. 2006;**26**:1135-1149

[41] Bennett GL, Hecht EM, Tanpitukpongse TP, Babb JS, Taouli B, Wong S, et al. MRI of the urethra in women with lower urinary tract symptoms: Spectrum of findings at static and dynamic imaging. American Journal of Roentgenology. 2009;**193**(6):1708- 1715. DOI: 10.2214/AJR.08.1547

[42] Catana C, Drzezga A, Heiss WD, Rosen BR. PET/MRI for neurologic applications. Journal of Nuclear Medicine. 2012;**53**(12):1916-1925. DOI: 10.2967/jnumed.112.105346

[43] Mier W, Mier D. Advantages in functional imaging of the brain. Frontiers in Human Neuroscience. 2015;**9**:249. DOI: 10.3389/fnhum.2015.00249

[44] Matsumoto S, Ishikawa A, Matsumoto S, Homma Y. Brain response provoked by different bladder volumes: A near infrared spectroscopy study. Neurourology and Urodynamics. 2011; **30**(4):529-535. DOI: 10.1002/nau.21016

**39**

symptoms.

**Chapter 4**

**Abstract**

Stress Urinary Incontinence: A

*Goran Mitulović, Thomas Mohr and Marianne Koch*

Proteomics research offers one strategy to elucidate the etiology of stress urinary

Stress urinary incontinence (SUI) is a disorder observed with the female population with widely varying prevalence, which is estimated to be 15–80%. The condition represents both a psychological and an economic burden, and it is expected that prevalence rates shall increase in the future, mainly due to increasing of life

While the classical epidemiology of SUI is understood quite well, many environmental and lifestyle risk factors leading to the condition have been identified. Among others, these are age, obesity, parity, vaginal delivery, and family history of SUI. Despite this much of the etiology of SUI remains unclear, and it is difficult to

Proteomic research offers one strategy to elucidate the etiology of SUI by identification of a significant and sufficient number of proteins, which provides the ability to avoid a preselection of candidate proteins. Many different serum, urine, and/or tissue protein markers have been investigated in the context of SUI. Almost all studies have targeted specific proteins as putative biomarkers, but with typically negative results. Prior studies have investigated a role for serum C-reactive protein, serum relaxin, and serum estradiol, without finding significant associations with

incontinence (SUI) by identification of a significant and sufficient number of proteins, which provides the ability to avoid a preselection of candidate proteins for a possible early detection of the SUI. SUI represents both a psychological as well as an economic burden, and prevalence rates are expected to increase in the future, due to increasing of life expectancy. The classical epidemiology of SUI is well understood, with many environmental and lifestyle risk factors identified, including age, obesity, parity, vaginal delivery, and family history. Despite this, much of the etiology of SUI remains unclear, and it is difficult to predict which women are at risk. This chapter shows some results based on proteomic analysis of the urine proteome, which might give the answer to the question on pathways activated in SUI. Besides proteins originating from the blood, urine contains proteins secreted from the inner wall of the bladder and the urethra, and these proteins might explain

**Keywords:** stress urinary incontinence, urinary proteome, proteomics

Proteomics Overview

the processes involved in genesis of SUI.

predict which women are at risk.

**1. Introduction**

expectancy.

#### **Chapter 4**

## Stress Urinary Incontinence: A Proteomics Overview

*Goran Mitulović, Thomas Mohr and Marianne Koch*

#### **Abstract**

Proteomics research offers one strategy to elucidate the etiology of stress urinary incontinence (SUI) by identification of a significant and sufficient number of proteins, which provides the ability to avoid a preselection of candidate proteins for a possible early detection of the SUI. SUI represents both a psychological as well as an economic burden, and prevalence rates are expected to increase in the future, due to increasing of life expectancy. The classical epidemiology of SUI is well understood, with many environmental and lifestyle risk factors identified, including age, obesity, parity, vaginal delivery, and family history. Despite this, much of the etiology of SUI remains unclear, and it is difficult to predict which women are at risk. This chapter shows some results based on proteomic analysis of the urine proteome, which might give the answer to the question on pathways activated in SUI. Besides proteins originating from the blood, urine contains proteins secreted from the inner wall of the bladder and the urethra, and these proteins might explain the processes involved in genesis of SUI.

**Keywords:** stress urinary incontinence, urinary proteome, proteomics

#### **1. Introduction**

Stress urinary incontinence (SUI) is a disorder observed with the female population with widely varying prevalence, which is estimated to be 15–80%. The condition represents both a psychological and an economic burden, and it is expected that prevalence rates shall increase in the future, mainly due to increasing of life expectancy.

While the classical epidemiology of SUI is understood quite well, many environmental and lifestyle risk factors leading to the condition have been identified. Among others, these are age, obesity, parity, vaginal delivery, and family history of SUI. Despite this much of the etiology of SUI remains unclear, and it is difficult to predict which women are at risk.

Proteomic research offers one strategy to elucidate the etiology of SUI by identification of a significant and sufficient number of proteins, which provides the ability to avoid a preselection of candidate proteins. Many different serum, urine, and/or tissue protein markers have been investigated in the context of SUI. Almost all studies have targeted specific proteins as putative biomarkers, but with typically negative results. Prior studies have investigated a role for serum C-reactive protein, serum relaxin, and serum estradiol, without finding significant associations with symptoms.

#### **2. Materials and methods**

#### **2.1 Samples**

In order to generate valid data and exclude possible false-positive and falsenegative samples being analyzed, urinary and serum samples from patients affected by stress incontinence cases and a proven history of symptoms of SUI for at least 3 months were obtained. This included a specific history of complaint of involuntary leakage on effort or exertion or on sneezing or coughing, a positive provocation stress test, which was defined as an observed transurethral loss of urine simultaneous with a cough or Valsalva maneuver at a bladder volume of minimum 300 ml. Furthermore, negative urine dipstick testing was necessary; all patients were older than 18 years and capable of independent toileting and having at least one previous vaginal delivery. In accordance with rules of the Medical University of Vienna, written informed consent was obtained from all participants. We excluded patients who had previous treatment for SUI (either surgical or pharmacological), a history of overactive bladder symptoms, and/or urinary incontinence other than SUI (tested using the ICIQ-UI Short Form questionnaire) [1]. In addition, a history of neurological disorders potentially affecting the urinary tract system, such as multiple sclerosis, Parkinson's disease, pelvic organ prolapse stage ≥ II (International Continence Society classification), clinically significant bladder outlet obstruction, and/or post-void residual volume > 100 ml, was also exclusion criteria. A series of other criteria were also observed, as described in Koch et al. [2]: the history of acute urinary retention or history of repeated catheterizations; history of bladder cancer or previous operation on the urinary tract; acute or recurrent urinary tract infection and/or hematuria; history of urinary tract stones, renal insufficiency, and hepatic disease; history of alcohol and/or drug abuse; pregnancy or lactation; and finally any patient with a serious medical condition.

Participants in the control group met identical criteria, but with no symptomatic SUI (ICIQ-short form score equal to 0) and negative cough stress test. Urine samples were obtained once only without requirement for a specific time of day. Participants were given a sterile urine cup (maximum 50 ml) and asked to deliver the first-void urine. In addition we retrieved blood samples from peripheral veins of all participants to determine their creatinine, transaminase, and bilirubin status. Urine samples were stored in the refrigerator at 4°C for a maximum of 1 hour before they were taken to the Clinical Institute of Laboratory Medicine (Proteomics Core Facility) for immediate processing.

#### **2.2 Proteomics sample preparation**

Trypsin for protein digestion was purchased from Promega Inc. (Vienna, Austria). Solvents for high-performance liquid chromatography (HPLC)—methanol (MeOH), acetonitrile (AcN), 2,2,2-trifluoroethanol (TFE), formic acid (FA), heptafluorobutyric acid (HFBA), iodoacetamide (IAA), triethyl bicarbonate (TEAB), and dithiothreitol—were purchased from Sigma-Aldrich (Vienna, Austria).

Protein precipitation from urine was performed according to the internally modified Wessel-Fluege method for protein precipitation, and all solvents were kept at −20°C. All working steps were performed on ice and centrifugation in a cooled centrifuge at +4°C. A sample volume of 2 ml of each urine sample was mixed with 6 ml methanol and 2 ml dichloromethane in a 50 ml Falcon tube, and samples were vigorously vortexed. After adding 6 ml of water to each sample, solutions were

**41**

*Stress Urinary Incontinence: A Proteomics Overview DOI: http://dx.doi.org/10.5772/intechopen.87178*

protocols [4–6].

vortexed another time. Samples were subsequently stored at −20°C for a minimum of 20 minutes for enhancement of protein precipitation. Phase separation was carried out by subsequent centrifugation for 5 minutes at 4500 rounds per minute (rpm). The upper layer of the solution was then carefully discarded while keeping the interphase and lower layer, and additional 6 ml of methanol were added prior to vigorous vortexing. Final centrifugation was performed for 5 minutes. The resulting supernatant was carefully removed, and the remaining protein pellet was dried on air. The dried protein pellet was later dissolved in 200 μl of 50 mM triethylammonium bicarbonate (TEAB) at pH 8.5. In cases where the protein pellet could not be properly dissolved in 200 μl of 50 mM TEAB, additional 50–1000 μl 50 mM TEAB were added, and the sample was sonicated by using the ultrasonic cell disruptor

Blood samples were prepared as described by Koch et al. [3]. Briefly, samples were immediately centrifuged to separate serum from blood cells and then frozen in separate vials at −20°C until further processing and an in-solution enzymatic digestion of all proteins extracted from both urinary and serum samples were achieved by applying a combination of Glu-C and trypsin (Promega, Vienna, Austria). This combination was selected in order to achieve improved sequence coverage for proteins. All steps for sample preparation were performed using previously published

Peptide separation was achieved using nano-high-performance liquid chromatography on a nano-RSLC Ultimate 3000 system (ThermoFisher Scientific, Vienna, Austria) using the PepMap C18 column (75 μm ID × 50 cm length, 3 μm ID, 100 Å pore size, ThermoFisher Scientific, Vienna, Austria). The separation column was mounted in a column oven and operated at 60°C. Prior to the separation on the nano-separation column, peptides were loaded onto a trap column (300 μm ID × 5 mm length, PepMap 300 Å pore size, ThermoFisher Scientific, Vienna, Austria). The analysis of biological samples bears the risk of carry-over and contamination of subsequent runs in cases where injected samples contained high amounts of peptides. Therefore, separation system was flushed between sample injections using the method developed earlier and described by Mitulovic et al. [7]. Optimization of loading conditions have been described in a number of other publications; however, we have used the conditions described in a paper by Schöbinger et al. where loading mobile phase was cooled to 3°C in order to enable improved peptide trapping on the

Details on separation gradient formation and mobile phases used are described

Mass spectrometric detection of digested peptides was performed using the maXis Impact time-of-flight (qToF) MS (Bruker, Bremen, Germany) equipped with the Captive Spray nano-electrospray source and operated at 1.6 kV; source temperature was set to 180°C for effective desolvatization of the analytes introduced from LC. Peptide masses were scanned in the range of m/z 300–m/z 2000, and 20 most intense signals were selected for MS/MS fragmentation. Fragmentation was performed by using collision-induced dissociation with nitrogen in the CID cell. Single-charged ions were excluded from MS/MS fragmentation, and those carrying charges of +2 to +4 were fragmented. In order to ensure fragmentation of a maximum number of ions, already fragmented masses were excluded from further fragmentation for 60 seconds but were allowed if the following MS/MS intensity was three times higher as compared to the previous MS/MS peak intensity. All

(Ultrasonic Cell Disruptor, Branson 5200, Dietzenbach, Germany).

**2.3 Chromatographic separation and detection**

trap column, which was operated at 60°C.

in publications by Koch et al. [2, 3].

*Stress Urinary Incontinence: A Proteomics Overview DOI: http://dx.doi.org/10.5772/intechopen.87178*

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

In order to generate valid data and exclude possible false-positive and falsenegative samples being analyzed, urinary and serum samples from patients affected by stress incontinence cases and a proven history of symptoms of SUI for at least 3 months were obtained. This included a specific history of complaint of involuntary leakage on effort or exertion or on sneezing or coughing, a positive provocation stress test, which was defined as an observed transurethral loss of urine simultaneous with a cough or Valsalva maneuver at a bladder volume of minimum 300 ml. Furthermore, negative urine dipstick testing was necessary; all patients were older than 18 years and capable of independent toileting and having at least one previous vaginal delivery. In accordance with rules of the Medical University of Vienna, written informed consent was obtained from all participants. We excluded patients who had previous treatment for SUI (either surgical or pharmacological), a history of overactive bladder symptoms, and/or urinary incontinence other than SUI (tested using the ICIQ-UI Short Form questionnaire) [1]. In addition, a history of neurological disorders potentially affecting the urinary tract system, such as multiple sclerosis, Parkinson's disease, pelvic organ prolapse stage ≥ II (International Continence Society classification), clinically significant bladder outlet obstruction, and/or post-void residual volume > 100 ml, was also exclusion criteria. A series of other criteria were also observed, as described in Koch et al. [2]: the history of acute urinary retention or history of repeated catheterizations; history of bladder cancer or previous operation on the urinary tract; acute or recurrent urinary tract infection and/or hematuria; history of urinary tract stones, renal insufficiency, and hepatic disease; history of alcohol and/or drug abuse; pregnancy or lactation; and finally

Participants in the control group met identical criteria, but with no symptomatic SUI (ICIQ-short form score equal to 0) and negative cough stress test. Urine samples were obtained once only without requirement for a specific time of day. Participants were given a sterile urine cup (maximum 50 ml) and asked to deliver the first-void urine. In addition we retrieved blood samples from peripheral veins of all participants to determine their creatinine, transaminase, and bilirubin status. Urine samples were stored in the refrigerator at 4°C for a maximum of 1 hour before they were taken to the Clinical Institute of Laboratory Medicine (Proteomics Core

Trypsin for protein digestion was purchased from Promega Inc. (Vienna, Austria). Solvents for high-performance liquid chromatography (HPLC)—methanol (MeOH), acetonitrile (AcN), 2,2,2-trifluoroethanol (TFE), formic acid (FA), heptafluorobutyric acid (HFBA), iodoacetamide (IAA), triethyl bicarbonate (TEAB), and dithiothreitol—were purchased from Sigma-Aldrich (Vienna,

Protein precipitation from urine was performed according to the internally modified Wessel-Fluege method for protein precipitation, and all solvents were kept at −20°C. All working steps were performed on ice and centrifugation in a cooled centrifuge at +4°C. A sample volume of 2 ml of each urine sample was mixed with 6 ml methanol and 2 ml dichloromethane in a 50 ml Falcon tube, and samples were vigorously vortexed. After adding 6 ml of water to each sample, solutions were

**2. Materials and methods**

any patient with a serious medical condition.

Facility) for immediate processing.

**2.2 Proteomics sample preparation**

**2.1 Samples**

**40**

Austria).

vortexed another time. Samples were subsequently stored at −20°C for a minimum of 20 minutes for enhancement of protein precipitation. Phase separation was carried out by subsequent centrifugation for 5 minutes at 4500 rounds per minute (rpm). The upper layer of the solution was then carefully discarded while keeping the interphase and lower layer, and additional 6 ml of methanol were added prior to vigorous vortexing. Final centrifugation was performed for 5 minutes. The resulting supernatant was carefully removed, and the remaining protein pellet was dried on air. The dried protein pellet was later dissolved in 200 μl of 50 mM triethylammonium bicarbonate (TEAB) at pH 8.5. In cases where the protein pellet could not be properly dissolved in 200 μl of 50 mM TEAB, additional 50–1000 μl 50 mM TEAB were added, and the sample was sonicated by using the ultrasonic cell disruptor (Ultrasonic Cell Disruptor, Branson 5200, Dietzenbach, Germany).

Blood samples were prepared as described by Koch et al. [3]. Briefly, samples were immediately centrifuged to separate serum from blood cells and then frozen in separate vials at −20°C until further processing and an in-solution enzymatic digestion of all proteins extracted from both urinary and serum samples were achieved by applying a combination of Glu-C and trypsin (Promega, Vienna, Austria). This combination was selected in order to achieve improved sequence coverage for proteins. All steps for sample preparation were performed using previously published protocols [4–6].

#### **2.3 Chromatographic separation and detection**

Peptide separation was achieved using nano-high-performance liquid chromatography on a nano-RSLC Ultimate 3000 system (ThermoFisher Scientific, Vienna, Austria) using the PepMap C18 column (75 μm ID × 50 cm length, 3 μm ID, 100 Å pore size, ThermoFisher Scientific, Vienna, Austria). The separation column was mounted in a column oven and operated at 60°C. Prior to the separation on the nano-separation column, peptides were loaded onto a trap column (300 μm ID × 5 mm length, PepMap 300 Å pore size, ThermoFisher Scientific, Vienna, Austria). The analysis of biological samples bears the risk of carry-over and contamination of subsequent runs in cases where injected samples contained high amounts of peptides. Therefore, separation system was flushed between sample injections using the method developed earlier and described by Mitulovic et al. [7]. Optimization of loading conditions have been described in a number of other publications; however, we have used the conditions described in a paper by Schöbinger et al. where loading mobile phase was cooled to 3°C in order to enable improved peptide trapping on the trap column, which was operated at 60°C.

Details on separation gradient formation and mobile phases used are described in publications by Koch et al. [2, 3].

Mass spectrometric detection of digested peptides was performed using the maXis Impact time-of-flight (qToF) MS (Bruker, Bremen, Germany) equipped with the Captive Spray nano-electrospray source and operated at 1.6 kV; source temperature was set to 180°C for effective desolvatization of the analytes introduced from LC. Peptide masses were scanned in the range of m/z 300–m/z 2000, and 20 most intense signals were selected for MS/MS fragmentation. Fragmentation was performed by using collision-induced dissociation with nitrogen in the CID cell. Single-charged ions were excluded from MS/MS fragmentation, and those carrying charges of +2 to +4 were fragmented. In order to ensure fragmentation of a maximum number of ions, already fragmented masses were excluded from further fragmentation for 60 seconds but were allowed if the following MS/MS intensity was three times higher as compared to the previous MS/MS peak intensity. All

measurements were performed in triplicate to provide corrections for technical variability of chromatographic separation and the ionization.

#### **2.4 Data analysis**

In order to identify proteins in analyzed sample, database search of mass spectrometric data was performed using the Human Swiss-Prot Database in its actual version at the time of analysis. Details of data search are described by Koch et al. [3]. Briefly, all searches were performed using Mascot v. 2.51 (http://www. matrixscience.com/). For the database search, trypsin and Glu-C were selected as enzymes with carbamidomethyl on Cys as fixed modification and oxidation on Met, phosphorylation on Ser, Thr, and Tyr as variable modifications.

Protein abundance was estimated by using peptide counts normalized to counts per million (cpm). Log2-fold change was estimated based on variance stabilized average log2 cpm values using the package edgeR. Resulting p values were corrected for multiple testing according to Burden et al. [8].

#### **3. Results**

Only proteins identified with at least two detected and identified peptides were selected for further analysis.

#### **3.1 Proteins identified in urinary samples**

The total number of identified individual proteins in the case group was 1459 and 2148 in the control group. The median number of identified proteins per urine sample was 377 (range 1167) in the case group and 417 (range 1197) in the control group.

Only 6 of the 828 proteins showed a significant difference in abundance in urine samples. This difference between SUI and controls was observed with a q-value <0.25. Out of these six identifications, three known proteins showed a higher abundance in SUI samples compared to controls: plasma serine protease inhibitor (logFC 1.11), leucine-rich alpha-2-glycoprotein (logFC 3.91), and lysosomal alphaglucosidase (logFC 1.24). From three uncharacterized proteins, one protein (gene symbol: PPIA) also showed higher abundance in SUI samples (logFC 1.96), whereas the other two uncharacterized proteins (gene symbol, UMOD; gene symbol, KIAA0586) presented a lower abundance in SUI samples than controls (logFC-4.87; logFC-1.99, respectively). **Table 1** shows the proteins identified in urinary samples with significant difference between the control and the case group.


**43**

**Figure 1.**

*Stress Urinary Incontinence: A Proteomics Overview DOI: http://dx.doi.org/10.5772/intechopen.87178*

laboratory without adaptations of existing hardware.

number of proteins shall be present in the urine.

protein (LRG1), and lysosomal alpha-glucosidase (GAA).

Current study is not the first one describing the urinary proteome [9–13]. However, this study was the first one to address specific clinical problem of SUI. The methodology used for both sample preparation and sample analysis was kept as simple as possible so that it can be easily reproduced in any proteomic

**Figure 1** shows the typical chromatogram for separation of tryptic peptides from a patient's urinary sample. The large number of peaks in the chromatogram indicates the presence of a large number of peptides. Database search revealed that in almost all cases of urinary proteomic analysis, the major proteins being identified are serum albumin and uromodulin. This is physiologically normal and common, although a common knowledge implies that no proteins or, at least, very low

Uromodulin, being the major urinary protein, was a major hit following serum

The abundance of all these proteins was found to be higher in SUI samples, and these are plasma serine protease inhibitor (SERPINA5), leucine-rich alpha-2-glyco-

The study identified six different, putative, probably SUI-specific urinary

The results showing the enrichment of mentioned proteins based on KEGG

SERPINA5 is usually present in urine in very low concentrations and serves, among other functions, as a pro-inflammatory factor, which might be an explanation for it overexpression in samples of patients with SUI [1, 14–20]. Furthermore, SERPINA5 was recently mentioned in a number of publications addressing diverse medical conditions, including pediatric leukemia, breast cancer, HIV infection, and hepatocellular carcinoma, which have identified a role played by SERPINA5 during

*UV Chromatogram trace at 210 nm showing the separation of tryptic peptides from urinary sample.*

**4. Discussion**

**4.1 Proteins identified**

proteins for the first time.

disease development [21–24].

pathway analysis are shown in **Figure 2**.

albumin.

**Table 1.**

*Proteins identified with a significantly different abundance in urine of patients with stress urinary incontinence (SUI) compared to control samples.*

### **4. Discussion**

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

variability of chromatographic separation and the ionization.

phosphorylation on Ser, Thr, and Tyr as variable modifications.

for multiple testing according to Burden et al. [8].

**3.1 Proteins identified in urinary samples**

**2.4 Data analysis**

**3. Results**

group.

selected for further analysis.

measurements were performed in triplicate to provide corrections for technical

In order to identify proteins in analyzed sample, database search of mass spectrometric data was performed using the Human Swiss-Prot Database in its actual version at the time of analysis. Details of data search are described by Koch et al. [3]. Briefly, all searches were performed using Mascot v. 2.51 (http://www. matrixscience.com/). For the database search, trypsin and Glu-C were selected as enzymes with carbamidomethyl on Cys as fixed modification and oxidation on Met,

Protein abundance was estimated by using peptide counts normalized to counts per million (cpm). Log2-fold change was estimated based on variance stabilized average log2 cpm values using the package edgeR. Resulting p values were corrected

Only proteins identified with at least two detected and identified peptides were

The total number of identified individual proteins in the case group was 1459 and 2148 in the control group. The median number of identified proteins per urine sample was 377 (range 1167) in the case group and 417 (range 1197) in the control

Only 6 of the 828 proteins showed a significant difference in abundance in urine samples. This difference between SUI and controls was observed with a q-value <0.25. Out of these six identifications, three known proteins showed a higher abundance in SUI samples compared to controls: plasma serine protease inhibitor (logFC 1.11), leucine-rich alpha-2-glycoprotein (logFC 3.91), and lysosomal alphaglucosidase (logFC 1.24). From three uncharacterized proteins, one protein (gene symbol: PPIA) also showed higher abundance in SUI samples (logFC 1.96), whereas

**Protein Gene symbol LogFC q-value** Plasma serine protease inhibitor SERPINA5 1.111 0.029 Leucine-rich alpha-2-glycoprotein LRG1 3.909 0.019 Lysosomal alpha-glycosidase GAA 1.237 0.062 Uromodulin UMOD −4.867 0.002 Peptidyl-prolyl cis-trans isomerase A PPIA 1.962 0.227 TALPID3 (KIAA0586) TALPID3 (KIAA0586) −1.992 0.227

the other two uncharacterized proteins (gene symbol, UMOD; gene symbol, KIAA0586) presented a lower abundance in SUI samples than controls (logFC-4.87; logFC-1.99, respectively). **Table 1** shows the proteins identified in urinary samples

*Proteins identified with a significantly different abundance in urine of patients with stress urinary* 

with significant difference between the control and the case group.

**42**

**Table 1.**

*incontinence (SUI) compared to control samples.*

Current study is not the first one describing the urinary proteome [9–13]. However, this study was the first one to address specific clinical problem of SUI. The methodology used for both sample preparation and sample analysis was kept as simple as possible so that it can be easily reproduced in any proteomic laboratory without adaptations of existing hardware.

**Figure 1** shows the typical chromatogram for separation of tryptic peptides from a patient's urinary sample. The large number of peaks in the chromatogram indicates the presence of a large number of peptides. Database search revealed that in almost all cases of urinary proteomic analysis, the major proteins being identified are serum albumin and uromodulin. This is physiologically normal and common, although a common knowledge implies that no proteins or, at least, very low number of proteins shall be present in the urine.

#### **4.1 Proteins identified**

Uromodulin, being the major urinary protein, was a major hit following serum albumin.

The study identified six different, putative, probably SUI-specific urinary proteins for the first time.

The abundance of all these proteins was found to be higher in SUI samples, and these are plasma serine protease inhibitor (SERPINA5), leucine-rich alpha-2-glycoprotein (LRG1), and lysosomal alpha-glucosidase (GAA).

The results showing the enrichment of mentioned proteins based on KEGG pathway analysis are shown in **Figure 2**.

SERPINA5 is usually present in urine in very low concentrations and serves, among other functions, as a pro-inflammatory factor, which might be an explanation for it overexpression in samples of patients with SUI [1, 14–20]. Furthermore, SERPINA5 was recently mentioned in a number of publications addressing diverse medical conditions, including pediatric leukemia, breast cancer, HIV infection, and hepatocellular carcinoma, which have identified a role played by SERPINA5 during disease development [21–24].

**Figure 1.** *UV Chromatogram trace at 210 nm showing the separation of tryptic peptides from urinary sample.*

#### *Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

#### **Figure 2.**

*KEGG pathway for the set of proteins with affected expression in SUI samples.*

Another protein, the leucine-rich alpha-2-glycoprotein, was also found to be increased in samples of SUI patients. This protein is secreted and normally present in plasma; however, it was also described to be involved in nonspecific inflammatory and cancer processes [25–28]. It has recently been described in the context of ulcerative colitis activity, pediatric, invasive bladder cancer, biliary tract cancer, lung cancer, pancreatic cancer, heart failure, neutrophilic granulocyte differentiation, and autoimmune diseases [29, 30].

Lysosomal alpha-glucosidase, another protein with increased expression in SUI samples, is essential for the degradation of glycogen to glucose in lysosomes, and it is present in, basically, all cells. Mutations in the respective gene result in Pompe disease, a severe and devastating glycogen storage disease caused by a deficiency in acid α-glucosidase. This condition is characterized by the lack of lysosomal alpha-glucosidase, which leads to intralysosomal accumulation of glycogen, the final consequence of which is the failure of the heart and skeletal muscles. The Pompe disease is being treated by enzyme replacement therapy. However, this is not sufficient, although it helps preventing assisted patients' ventilation and ensuring a ventilation-free survival. GAA is an enzyme that is essential for lysosomal glycogen hydrolysis, and the protein has also been identified as a potential biomarker for gut wall integrity in infants with necrotizing enterocolitis, an inflammatory process involving the intestinal tissue [31]. GAA has not been described as a factor for SUI, but the involvement of GAA in pathologies of smooth muscle [32] suggests that this protein might have an important role for the proper function of the bladder. Niedworok et al. [33] suggested that GAA might be involved in bladder cancer as an endogenous inhibitor of bladder cancer cell proliferation. The authors concluded that GAA is upregulated in response to antiproliferative tyrosine kinase inhibitors. That would mean that high biglycan expression is associated with favorable prognosis for patients with bladder cancer.

Alsaikhan et al. [34] investigated the partial bladder obstruction and the expression, among other factors, of GAA. Authors describe that small leucine-rich proteoglycans, required for collagen fibrillogenesis showed a significant reduction, which was consistent with a pro-fibrotic environment and deregulated collagen assembly. Although this study did not address the matter of incontinence, it showed that leucine-rich proteoglycans have an important role to play for the regulation of bladder function.

A similar observation was made by Appunni et al. [35, 36] for the role of leucine-rich proteoglycans and the bladder cancer. Leucine-rich proteoglycans are not only required in the matrix for structural framework, but they also show to be effective in controlling various physiological functions. Among these functions are also the cell cycle regulation and the leucine-rich proteoglycans which perform the role of the guardians of the cellular matrix.

**45**

*Stress Urinary Incontinence: A Proteomics Overview DOI: http://dx.doi.org/10.5772/intechopen.87178*

noma [31].

Upon database search and quantitation, peptidyl-prolyl cis-trans isomerase A (PPIA) was found to be overexpressed. This protein has been described to be involved in inflammatory processes and immunomodulation and induction of interleukin-6 release from macrophages. Recent publications have discussed an involvement in type 2 diabetes mellitus, vascular disease, and gastric adenocarci-

Two of the identified uncharacterized proteins, which are encoded by associated

with the genes UMOD and KIAA0586, showed lower expression in SUI samples. UMOD encodes for the protein uromodulin, which is, among other functions, involved in the prevention of urinary tract infection, water/electrolyte balance, and kidney innate immunity. Uromodulin is usually highly abundant in the urine of healthy humans, and, as mentioned previously, it is the most abundant protein in normal urine [37]. Interestingly, uromodulin is another glycoprotein identified to have different expression patterns in SUI samples as compared to control samples. UMOD is a GPI-anchored glycoprotein produced by the kidney but not derived from the blood. The function of these proteins is still not well understood, but it is taught to be linked to the water/electrolyte balance and kidney innate immunity. Hypertension in pregnancy was associated with a decrease in the uromodulin's excretion rate [38], and the results of SUI samples also revealed that the level of uromodulin was decreased. Furthermore, UMOD can be used as a predictive factor for preeclampsia [39]. UMOD has been described to prevent the binding of the IgG light chain to their putative receptors [40]. Da Silva et al. described the role of UMOD as an allergen epitope [41] for activation of the allergy-associated T cells in mouse. There is no description of causality in humans; however, the lower expression of this protein in samples of SUI patients might be of importance considering

KIAA0586 encodes for the protein TALPID3, which is required for ciliogenesis and sonic hedgehog/SHH signaling [42–48]. Fleming et al. [49] described the possible involvement of TALPID3 in kidney damage in patients with Joubert syndrome. Interestingly, all patients enrolled in this study and having a mutation on KIAA05866 gene, which encodes for TALPID3, showed to have significantly better chances of preserving the kidneys, which are, otherwise, affected by the Joubert syndrome. It is still unclear why this protein was identified with a decreased

Another protein that was ubiquitous in all samples was keratin. Keratin is commonly identified during proteomics analysis, and it often serves as a quality control of the analysis, if not present in high amounts. However, more often, keratin is considered being a contaminant and something that shall be kept out of the sample

Therefore, requirements were taken to exclude any possible contamination with keratin, but it was still identified in large amount in all samples. Besides being considered a contaminant for proteomics experiments, keratin is an important part

The best chance to identify these proteins will be by investigating the known functions, tissue specificities, and interactions of the specific proteins identified in samples of SUI patients. It is also important to gain a detailed insight into potential mechanisms of the pathophysiology and etiology of SUI, which seem to depend on many factors and might be a complex process depending on more physiological processes taking place in the urinary bladder. Proteins, which were identified with

of the urinary proteome which seems to be present in all collected samples. As for now, no biomarkers have yet been identified for SUI, and it is rather improbable that a single protein will be a marker. A more probable scenario is that a group of proteins with a significantly different abundance in SUI patients compared

the function of the smooth muscle of the urinary bladder.

abundancy in samples of SUI patients.

to controls will be defined as putative markers.

by any means.

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

*KEGG pathway for the set of proteins with affected expression in SUI samples.*

tion, and autoimmune diseases [29, 30].

**Figure 2.**

Another protein, the leucine-rich alpha-2-glycoprotein, was also found to be increased in samples of SUI patients. This protein is secreted and normally present in plasma; however, it was also described to be involved in nonspecific inflammatory and cancer processes [25–28]. It has recently been described in the context of ulcerative colitis activity, pediatric, invasive bladder cancer, biliary tract cancer, lung cancer, pancreatic cancer, heart failure, neutrophilic granulocyte differentia-

Lysosomal alpha-glucosidase, another protein with increased expression in SUI samples, is essential for the degradation of glycogen to glucose in lysosomes, and it is present in, basically, all cells. Mutations in the respective gene result in Pompe disease, a severe and devastating glycogen storage disease caused by a deficiency in acid α-glucosidase. This condition is characterized by the lack of lysosomal alpha-glucosidase, which leads to intralysosomal accumulation of glycogen, the final consequence of which is the failure of the heart and skeletal muscles. The Pompe disease is being treated by enzyme replacement therapy. However, this is not sufficient, although it helps preventing assisted patients' ventilation and ensuring a ventilation-free survival. GAA is an enzyme that is essential for lysosomal glycogen hydrolysis, and the protein has also been identified as a potential biomarker for gut wall integrity in infants with necrotizing enterocolitis, an inflammatory process involving the intestinal tissue [31]. GAA has not been described as a factor for SUI, but the involvement of GAA in pathologies of smooth muscle [32] suggests that this protein might have an important role for the proper function of the bladder. Niedworok et al. [33] suggested that GAA might be involved in bladder cancer as an endogenous inhibitor of bladder cancer cell proliferation. The authors concluded that GAA is upregulated in response to antiproliferative tyrosine kinase inhibitors. That would mean that high biglycan expression is associated with favorable prognosis for patients with bladder cancer. Alsaikhan et al. [34] investigated the partial bladder obstruction and the expression, among other factors, of GAA. Authors describe that small leucine-rich proteoglycans, required for collagen fibrillogenesis showed a significant reduction, which was consistent with a pro-fibrotic environment and deregulated collagen assembly. Although this study did not address the matter of incontinence, it showed that leucine-rich proteoglycans have an important role to play for the regulation of

A similar observation was made by Appunni et al. [35, 36] for the role of leucine-rich proteoglycans and the bladder cancer. Leucine-rich proteoglycans are not only required in the matrix for structural framework, but they also show to be effective in controlling various physiological functions. Among these functions are also the cell cycle regulation and the leucine-rich proteoglycans which perform the

**44**

bladder function.

role of the guardians of the cellular matrix.

Upon database search and quantitation, peptidyl-prolyl cis-trans isomerase A (PPIA) was found to be overexpressed. This protein has been described to be involved in inflammatory processes and immunomodulation and induction of interleukin-6 release from macrophages. Recent publications have discussed an involvement in type 2 diabetes mellitus, vascular disease, and gastric adenocarcinoma [31].

Two of the identified uncharacterized proteins, which are encoded by associated with the genes UMOD and KIAA0586, showed lower expression in SUI samples.

UMOD encodes for the protein uromodulin, which is, among other functions, involved in the prevention of urinary tract infection, water/electrolyte balance, and kidney innate immunity. Uromodulin is usually highly abundant in the urine of healthy humans, and, as mentioned previously, it is the most abundant protein in normal urine [37]. Interestingly, uromodulin is another glycoprotein identified to have different expression patterns in SUI samples as compared to control samples. UMOD is a GPI-anchored glycoprotein produced by the kidney but not derived from the blood. The function of these proteins is still not well understood, but it is taught to be linked to the water/electrolyte balance and kidney innate immunity. Hypertension in pregnancy was associated with a decrease in the uromodulin's excretion rate [38], and the results of SUI samples also revealed that the level of uromodulin was decreased. Furthermore, UMOD can be used as a predictive factor for preeclampsia [39]. UMOD has been described to prevent the binding of the IgG light chain to their putative receptors [40]. Da Silva et al. described the role of UMOD as an allergen epitope [41] for activation of the allergy-associated T cells in mouse. There is no description of causality in humans; however, the lower expression of this protein in samples of SUI patients might be of importance considering the function of the smooth muscle of the urinary bladder.

KIAA0586 encodes for the protein TALPID3, which is required for ciliogenesis and sonic hedgehog/SHH signaling [42–48]. Fleming et al. [49] described the possible involvement of TALPID3 in kidney damage in patients with Joubert syndrome. Interestingly, all patients enrolled in this study and having a mutation on KIAA05866 gene, which encodes for TALPID3, showed to have significantly better chances of preserving the kidneys, which are, otherwise, affected by the Joubert syndrome. It is still unclear why this protein was identified with a decreased abundancy in samples of SUI patients.

Another protein that was ubiquitous in all samples was keratin. Keratin is commonly identified during proteomics analysis, and it often serves as a quality control of the analysis, if not present in high amounts. However, more often, keratin is considered being a contaminant and something that shall be kept out of the sample by any means.

Therefore, requirements were taken to exclude any possible contamination with keratin, but it was still identified in large amount in all samples. Besides being considered a contaminant for proteomics experiments, keratin is an important part of the urinary proteome which seems to be present in all collected samples.

As for now, no biomarkers have yet been identified for SUI, and it is rather improbable that a single protein will be a marker. A more probable scenario is that a group of proteins with a significantly different abundance in SUI patients compared to controls will be defined as putative markers.

The best chance to identify these proteins will be by investigating the known functions, tissue specificities, and interactions of the specific proteins identified in samples of SUI patients. It is also important to gain a detailed insight into potential mechanisms of the pathophysiology and etiology of SUI, which seem to depend on many factors and might be a complex process depending on more physiological processes taking place in the urinary bladder. Proteins, which were identified with

significantly higher abundance in SUI samples, have been described earlier as active participants in inflammatory processes and cancer development. On the other hand, proteins that were identified and quantified with a significantly lower abundance usually seem to have a protective effect in the urinary tract system although we cannot be explained at the current time.

#### **5. Conclusion**

It is important to stress out that one of the most important factors for a successful analysis is the selection of samples to be analyzed. It is very important to include urine samples retrieved from a population with very strict inclusion and exclusion criteria in order to avoid confounding factors. Urine samples must be processed according to a standardized protocol within a short time frame after collection.

Although a thorough map of the human proteome has been described, and made available to researchers [50], this map is still not complete and it is prone to errors and biases. Therefore, the incomplete "humane proteome mapping" is an additional challenge despite efforts of the research community to identify and characterize all human proteins.

By investigating the urinary proteome at one time point only, no conclusion can be made on whether the significantly differently expressed proteins are a consequence of the pathological process or whether they themselves are directly involved in causal processes.

Therefore, due to the characteristics of the identified proteins, it can be said that inflammatory processes may be involved in the etiology of SUI. However, the relevance of these findings regarding the pathogenesis of SUI needs to be broadly investigated, and the results described need to be replicated in a different population and at different time points.

#### **Author details**

Goran Mitulović1,2\*, Thomas Mohr3 and Marianne Koch4

1 Clinical Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

2 Proteomic Core Facility, Medical University of Vienna, Vienna, Austria

3 Science Consult Thomas Mohr KG, Guntramsdorf, Austria

4 Clinical Division of General, Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria

\*Address all correspondence to: goran.mitulovic@meduniwien.ac.at

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**47**

*Stress Urinary Incontinence: A Proteomics Overview DOI: http://dx.doi.org/10.5772/intechopen.87178*

[1] Johannessen HH, Stafne SN, Falk RS,

[9] Aregger F, Uehlinger DE, Witowski J, Brunisholz RA, Hunziker P, Frey FJ, et al. Identification of IGFBP-7 by urinary proteomics as a novel prognostic marker in early acute kidney injury. Kidney International.

[10] Court M, Selevsek N, Matondo M, Allory Y, Garin J, Masselon CD, et al. Toward a standardized urine proteome analysis methodology. Proteomics.

Chaerkady R, Subbannayya Y, Nanjappa V, Kumar P, et al. A comprehensive map of the human urinary proteome. Journal of Proteome Research.

[12] Nagaraj N, Mann M. Quantitative analysis of the intra- and interindividual variability of the normal urinary proteome. Journal of Proteome

Research. 2011;**10**(2):637-645

[13] Marimuthu A, O'Meally RN,

Chaerkady R, Subbannayya Y, Nanjappa V, Kumar P, et al. A comprehensive map of the human urinary proteome. Journal of Proteome Research.

[14] Colla C, Paiva LL, Ferla L, Trento MJB, de Vargas IMP, Dos Santos BA, et al. Pelvic floor dysfunction in the immediate puerperium, and 1 and 3 months after vaginal or cesarean delivery. International Journal of Gynaecology and Obstetrics.

[15] Li YT, Lee WL. Is it really risky for postpartum stress urinary incontinence in the first year postpartum. Journal of the Chinese Medical Association: JCMA.

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Stordahl A, Wibe A, Morkved S. Prevalence and predictors of double incontinence 1 year after first delivery. International Urogynecology Journal.

[2] Koch M, Mitulovic G, Hanzal E, Umek W, Seyfert S, Mohr T, et al. Urinary proteomic pattern in female stress urinary incontinence: A pilot study. International Urogynecology Journal. Nov 2016;**27**(11):1729-1734

[3] Koch M, Umek W, Hanzal E, Mohr T,

[5] Schöbinger M, Klein OJ, Mitulović G.

Seyfert S, Koelbl H, et al. Serum proteomic pattern in female stress urinary incontinence. Electrophoresis.

[4] Fichtenbaum A, Schmid R, Mitulović G. Direct injection of HILIC fractions on the reversedphase trap column improves protein identification rates for salivary proteins. Electrophoresis. 2016;**37**(22):2922-2929

Low-temperature mobile phase for peptide trapping at elevated separation temperature prior to nano RP-HPLC–MS/MS. Separations.

[6] Mitulovic G, Panic-Jankovic T, Pietrowski D, Gorshkov M, Schmid R. Analyzing the preimplantation secretome of human embryos. FEBS

[7] Mitulović G, Stingl C, Steinmacher I,

Hudecz O, Hutchins JRA, Peters J-M, et al. Preventing carryover of peptides and proteins in nano LC-MS separations. Analytical Chemistry.

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*Stress Urinary Incontinence: A Proteomics Overview DOI: http://dx.doi.org/10.5772/intechopen.87178*

#### **References**

*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

we cannot be explained at the current time.

**5. Conclusion**

human proteins.

in causal processes.

**Author details**

Vienna, Austria

tion and at different time points.

Goran Mitulović1,2\*, Thomas Mohr3

provided the original work is properly cited.

significantly higher abundance in SUI samples, have been described earlier as active participants in inflammatory processes and cancer development. On the other hand, proteins that were identified and quantified with a significantly lower abundance usually seem to have a protective effect in the urinary tract system although

It is important to stress out that one of the most important factors for a successful analysis is the selection of samples to be analyzed. It is very important to include urine samples retrieved from a population with very strict inclusion and exclusion criteria in order to avoid confounding factors. Urine samples must be processed according to a standardized protocol within a short time frame after collection.

Although a thorough map of the human proteome has been described, and made available to researchers [50], this map is still not complete and it is prone to errors and biases. Therefore, the incomplete "humane proteome mapping" is an additional challenge despite efforts of the research community to identify and characterize all

By investigating the urinary proteome at one time point only, no conclusion can be made on whether the significantly differently expressed proteins are a consequence of the pathological process or whether they themselves are directly involved

Therefore, due to the characteristics of the identified proteins, it can be said that inflammatory processes may be involved in the etiology of SUI. However, the relevance of these findings regarding the pathogenesis of SUI needs to be broadly investigated, and the results described need to be replicated in a different popula-

and Marianne Koch4

1 Clinical Department of Laboratory Medicine, Medical University of Vienna,

4 Clinical Division of General, Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Proteomic Core Facility, Medical University of Vienna, Vienna, Austria

\*Address all correspondence to: goran.mitulovic@meduniwien.ac.at

3 Science Consult Thomas Mohr KG, Guntramsdorf, Austria

**46**

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*Stress Urinary Incontinence: A Proteomics Overview DOI: http://dx.doi.org/10.5772/intechopen.87178*

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Reproductive Biology. 1993;**48**(1):23-31

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*Lower Urinary Tract Dysfunction - From Evidence to Clinical Practice*

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[24] Haynes BP, Viale G, Galimberti V, Rotmensz N, Gibelli B, Smith IE, et al. Differences in expression of proliferation-associated genes and RANKL across the menstrual cycle in estrogen receptor-positive primary breast cancer. Breast Cancer Research and Treatment. 2014;**148**(2):327-335

[25] Smith C, Batruch I, Bauca J, Kosanam H, Ridley J, Bernardini M, et al. Deciphering the peptidome of urine from ovarian cancer patients and healthy controls. Clinical Proteomics.

[26] Tung CL, Lin ST, Chou HC, Chen YW, Lin HC, Tung CL, et al. Proteomics-based identification of plasma biomarkers in oral squamous cell carcinoma. Journal of Pharmaceutical and Biomedical Analysis. 2013;**75**:7-17

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women before and during pregnancy: Prevalence, incidence, type, and risk factors. International Urogynecology

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[18] Volloyhaug I, van Gruting I, van Delft K, Sultan AH, Thakar R. Is bladder neck and urethral mobility associated with urinary incontinence and mode of delivery 4 years after childbirth? Neurourology and Urodynamics.

Journal. 2018;**29**(3):353-362

2017;**80**(8):498-502

2017;**36**(5):1403-1410

2014;**67**(4):323-330

2012;**119**(11):1361-1369

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[20] Gartland D, Donath S, MacArthur C, Brown SJ. The onset, recurrence and associated obstetric risk factors for urinary incontinence in the first 18 months after a first birth: An Australian nulliparous cohort study. BJOG : An International Journal of Obstetrics and Gynaecology.

[21] Kawahara R, Bollinger JG, Rivera C, Ribeiro AC, Brandao TB, Paes Leme AF, et al. A targeted proteomic strategy for the measurement of oral cancer candidate biomarkers in human saliva.

[22] Priola GM, Foster MW, Deal AM, Richardson BM, Thompson JW, Blatt J. Cerebrospinal fluid proteomics in children during induction for acute lymphoblastic leukemia: A pilot

Proteomics. 2016;**16**(1):159-173

**48**

[29] Serada S, Fujimoto M, Ogata A, Terabe F, Hirano T, Iijima H, et al. iTRAQ-based proteomic identification of leucine-rich alpha-2 glycoprotein as a novel inflammatory biomarker in autoimmune diseases. Annals of the Rheumatic Diseases. 2010;**69**(4):770-774

[30] Serada S, Fujimoto M, Terabe F, Iijima H, Shinzaki S, Matsuzaki S, et al. Serum leucine-rich alpha-2 glycoprotein is a disease activity biomarker in ulcerative colitis. Inflammatory Bowel Diseases. 2012;**18**(11):2169-2179

[31] Ramachandran S, Venugopal A, Kutty VR, A V GD, Chitrasree V, et al. Plasma level of cyclophilin A is increased in patients with type 2 diabetes mellitus and suggests presence of vascular disease. Cardiovascular Diabetology. 2014;**13**:38

[32] McCall AL, Salemi J, Bhanap P, Strickland LM, Elmallah MK. The impact of Pompe disease on smooth muscle: A review. Journal of Smooth Muscle Research. 2018;**54**:100-118

[33] Niedworok C, Röck K, Kretschmer I, Freudenberger T, Nagy N, Szarvas T, et al. Inhibitory role of the small leucinerich proteoglycan biglycan in bladder cancer. PLoS One. 2013;**8**(11):e80084

[34] Alsaikhan B, Fahlman R, Ding J, Tredget E, Metcalfe PD. Proteomic profile of an acute partial bladder outlet obstruction. Canadian Urological Association Journal—Journal de l'Association des urologues du Canada. 2015;**9**(3-4):E114-EE21

[35] Appunni S, Anand V, Khandelwal M, Gupta N, Rubens M, Sharma A. Small Leucine Rich Proteoglycans (decorin, biglycan and lumican) in cancer. Clinica Chimica Acta. 2019;**491**:1-7

[36] Appunni S, Anand V, Khandelwal M, Seth A, Mathur S, Sharma A. Altered expression of small leucinerich proteoglycans (Decorin,

Biglycan and Lumican): Plausible diagnostic marker in urothelial carcinoma of bladder. Tumor Biology. 2017;**39**(5):1010428317699112

[37] Liu M, Chen Y, Liang Y, Liu Y, Wang S, Hou P, et al. Novel UMOD mutations in familial juvenile hyperuricemic nephropathy lead to abnormal uromodulin intracellular trafficking. Gene. 2013;**531**(2):363-369

[38] Nesselhut T, Rath W, Grunow E, Kaufholz G, Ostermai U, Cillien N, et al. The relationship between urinary Tamm-Horsfall glycoprotein excretion and urinary activity of glycosidases in normal pregnancy and pre-eclampsia. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 1993;**48**(1):23-31

[39] Carty DM, Siwy J, Brennand JE, Zürbig P, Mullen W, Franke J, et al. Urinary proteomics for prediction of preeclampsia. Hypertension. 2011;**57**(3):561-569

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[43] Ojeda Naharros I, Cristian FB, Zang J, Gesemann M, Ingham PW, Neuhauss SCF, et al. The ciliopathy protein TALPID3/KIAA0586 acts upstream

of Rab8 activation in zebrafish photoreceptor outer segment formation and maintenance. Scientific Reports. 2018;**8**(1):2211

of the human proteome. Nature. 2014;**509**(7502):575-581

**51**

Section 3

Management

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Section 3
