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Afferent Neurourology: An Epidemiological Perspective
Afferent Neurourology: An Epidemiological Perspective J. Quentin Clemens* From the Department of Urology, University of Michigan Medical Center, Ann Arbor, Michigan
Abbreviations and Acronyms CP ⫽ chronic prostatitis CPPS ⫽ chronic pelvic pain syndrome GU ⫽ genitourinary IC ⫽ interstitial cystitis LUTS ⫽ lower urinary tract symptoms NHS ⫽ Nurses’ Health Study NIH ⫽ National Institutes of Health OAB ⫽ overactive bladder PBS ⫽ painful bladder syndrome Submitted for publication September 22, 2009. * Correspondence: Department of Urology, University of Michigan Medical Center, 1500 East Medical Center Dr., Ann Arbor, Michigan 481095330 (telephone: 734-232-4881; FAX: 734-9369127; e-mail: [email protected]). Supplementary material for this article can be obtained at http://www.med.umich.edu/urology/ research/ManuscriptAppendices/index.html.
Purpose: Multiple urological conditions are characterized by bothersome sensations such as pain or urinary urgency. There is significant confusion about the etiology and pattern of these symptoms. Materials and Methods: The term afferent neurourology is introduced to describe the study of sensory processing related to the genitourinary tract. Epidemiological studies related to afferent neurourology are reviewed and unique challenges to our understanding of these disorders are described. Results: Afferent urological disorders are characterized by urological pain or urinary urgency. Conceptually these afferent disorders can be differentiated from efferent urological disorders and structural urological abnormalities. Afferent urological disorders are common in men and women, although symptom severity is variable. Study of the entire disease spectrum may provide insight into pathogenesis and prevention. The natural history of these symptoms is poorly understood. Afferent urological disorders commonly co-occur with other poorly understood somatic symptoms, suggesting that symptoms may be due to a systemic disorder in certain individuals. Mechanisms responsible for these sensory abnormalities are poorly understood and may arise from central and peripheral abnormalities. Conclusions: Urinary pain and urgency are common, bothersome symptoms that are currently understood poorly and managed ineffectively. Intentional recognition of sensory urological abnormalities as a separate field of study may enhance research efforts into these conditions and improve treatment outcomes. Key Words: urinary bladder; cystitis, interstitial; pain; prostatitis; epidemiology
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NEUROUROLOGY encompasses the study of lower urinary tract neurophysiology and the functional urological abnormalities that result from neurological dysfunction, disease or injury. Multiple neurological disorders can adversely affect urinary tract function. Management principles focus on preserving continence and preventing upper urinary tract complications by decreasing detrusor overactivity and maintaining low bladder storage pressure. Therefore, the focus is on identifying and treating abnormal motor (efferent) neurological activity.
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0022-5347/10/1842-0432/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
A Novel Paradigm A different type of abnormality exists in which bothersome sensations of pain or urinary urgency are the defining complaints. For these conditions the concept of afferent neurourology has been introduced.1 This term refers to the field of study concerned with the processing of sensory information related to the GU tract. This review expands on this concept to discuss specific epidemiological data that are relevant to the field of afferent
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Vol. 184, 432-439, August 2010 Printed in U.S.A. DOI:10.1016/j.juro.2010.04.012
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neurourology. This information may focus attention and research on this poorly understood field. Defining Characteristics of Disorders The abnormal processing of sensory information that characterizes afferent neurourology results in pain and urinary urgency symptoms. Pain may be described by patients as pressure or discomfort but such symptoms still meet the accepted definition of pain, that is an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage.2 Urinary frequency and nocturia are often but not always present. However, frequency and nocturia are behaviors, rather than sensory experiences, that are caused by urinary urgency, pain and many other factors, such as fluid intake, medical conditions, medication etc. Therefore, frequency and nocturia are not considered defining characteristics in the afferent neurourology paradigm. Clinical Syndromes Urological pain and urgency result in clinically recognized conditions such as IC/PBS, CP/CPPS, OAB, LUTS, chronic epididymitis and orchialgia. Each is a syndrome (collection of symptoms) without objective markers. It is common for individuals to have symptoms that meet the criteria for more than 1 of these conditions. OAB can be subcategorized into OAB dry (urgency without urge incontinence) and OAB wet (urgency with urge incontinence). These 2 subgroups are typically considered part of an OAB disease spectrum but to my knowledge it is unknown whether they in fact share the same underlying pathophysiology. It is also unclear to what extent those with OAB dry progress to OAB wet. Furthermore, the mechanism responsible for converting the afferent symptom of urgency to the efferent symptom of urge incontinence is not well understood. Afferent symptoms and disorders can be differentiated from efferent abnormalities (eg detrusor failure, decreased bladder compliance and detrusor overactivity) and structural abnormalities (eg stress incontinence, prolapse and anatomical bladder outlet obstruction) (see Appendix). Efferent and structural abnormalities tend to be better understood because each has an objective diagnostic test that can be done to confirm the diagnosis and quantify severity. Conversely the lack of objective markers for afferent disorders has hampered our ability to confirm the diagnosis, identify patient subgroups or provide prognostic information. Furthermore, multiple afferent, efferent and structural disorders may be present in an individual.
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LOWER URINARY TRACT SYMPTOMS Traditionally the term LUTS has referred to symptoms attributable to benign prostatic hyperplasia. However, there is growing recognition that a more expansive underlying pathophysiology than the prostate alone is responsible for these symptoms.3 For example, LUTS are equally common in men and women.4 The LUTS concept combines various symptoms that are typically subcategorized as voiding symptoms (incomplete bladder emptying, intermittence, slow stream and straining to void) and storage symptoms (frequency, urgency and nocturia). This concept is fairly comprehensive of common urological symptoms and LUTS symptoms are commonly quantified and used to measure symptom severity. However, the LUTS paradigm ignores pain, which is often present in patients with LUTS.5,6 Furthermore, subcategorization into voiding and storage symptoms implicitly acknowledges the disparate nature of these symptom types. Thus, 2 patients with the same degree of LUTS based on a symptom score may show completely different symptom characteristics. Also, the more specific subcategory of storage symptoms includes a symptom (urgency) and behaviors (frequency and nocturia) that may be completely unrelated, as explained. In the afferent neurourology paradigm urgency and pain symptoms are isolated as unique sensory abnormalities.
AFFERENT UROLOGICAL DISORDER PREVALENCE Generally prevalence studies of afferent urological disorders have been done in 1 of 5 ways. Collectively an impression about the overall prevalence of these conditions can be formed. 1) Surveys have been done that ask participants whether they have ever been diagnosed with a condition of interest (self-report studies). Such studies are subject to recall bias and depend on accurate clinical diagnoses being communicated to patients. 2) Questionnaires have been administered to identify symptoms suggestive of the condition of interest (symptom assessments). These studies are often subject to response bias since individuals with the symptoms may be more likely to complete the questionnaire. Also, identifying symptoms is not the same as diagnosing a specific medical condition, and to our knowledge the sensitivity and specificity of various questionnaire definitions for these conditions are unknown. 3) Administrative billing data have been used to identify individuals in a population with a specific diagnosis indicating an afferent urological disorder (clinician diagnosis). These studies require an accurate clinician diagnosis and are limited by the categorization schemes that are inclusive in billing data. 4) Clinical records
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have been reviewed to identify the number of patients seen with certain diagnoses (clinical prevalence). These studies estimate disease prevalence in a clinical population but do not provide a true population prevalence estimate. 5) Office visits for a particular condition have been counted to estimate disease prevalence (office visits). Data in these studies tend to be fairly reliable since they are obtained directly from caregivers soon after the office visit. However, these studies are limited to clinical patients and do not identify individuals with the conditions. Instead they count the total number of office visits for a particular condition. Also, the sampling time frame is short. Thus, this type of study may not generate reliable data for medical diagnoses that are fairly uncommon. Self-Report Studies Two large-scale studies in the United States have used self-report to estimate the IC/PBS prevalence.7 The first study was done as part of the 1989 National Health Interview Survey and the second was part of the National Health and Nutrition Examination Survey III, done between 1988 and 1994. The same definition of IC/PBS was used in each. Participants were asked, “Have you ever had symptoms of a bladder infection (such as pain in your bladder and frequent urination) that lasted more than 3 months?” Those who gave a positive response were then asked, “When you had this condition, were you told that you had interstitial cystitis or painful bladder syndrome?” An affirmative answer to the 2 questions was considered to define IC/ PBS. Prevalence estimates obtained from these 2 studies were virtually identical. In the National Health Interview Survey the overall prevalence was 500/100,000 population and the prevalence in women was 865/100,000. In the National Health and Nutrition Examination Survey III the prevalence was 470/100,000 population, including 60/100,000 men and 850/100,000 women. This equals approximately 83,000 men and 1.2 million women in the United States. Four population based self-report studies of prostatitis have been done. A total of 31,681 male participants in the United States Health Professionals Follow-Up Study in 1992 were asked, “Have you ever had prostatitis or a prostatic infection?”8 A positive response was obtained in 16% of respondents. A study in 1,832 men in Finland inquired about a previous diagnosis of prostatitis and identified a 14.2% prevalence rate.9 Based on questionnaires administered to 703 black American men as part of the Flint Men’s Health Study 6.7% reported a history of physician diagnosed prostatitis.10 Finally, a survey of 184 members of a United States National Guard Unit comprising 20 to 49-
year-old men identified 5% with self-reported prostatitis.11 Based on concerns about industrial exposure and the risk of epididymitis in 1992 a survey of 1,342 male textile workers was done.12 Of respondents 11.1% reported having had testicular pain severe enough to consult a physician, 6.4% reported a history of epididymitis and 1.3% reported a history of orchitis. No additional clinical data were obtained to differentiate acute from chronic complaints. To my knowledge no self-report prevalence studies of OAB have been done to date. Symptoms (see supplementary material) IC/PBS. Multiple population based studies have estimated the prevalence of IC/PBS symptoms. Since the studies used different case definitions, it is difficult to make comparisons across them. Also, sampling strategies and response rates varied considerably. The prevalence estimate in Europe is approximately 0.5% in women while in the United States it is 1% to 11% with most estimates in the 1% to 2% range. The prevalence in men is typically 2 to 3-fold less than in women. Prostatitis. Numerous prevalence studies have also been done to identify prostatitis-like symptoms. Unlike similar studies of IC/PBS, many prostatitis studies have used a standard definition to identify symptoms. As originally proposed by Nickel et al,13 this definition uses responses from the NIH CP Symptom Index to define prostatitis symptoms as perineal or ejaculatory pain plus a score of 4 or greater on the NIH CP Symptom Index pain subscale. Using a standard definition permits better comparisons across various studies, although other factors such as respondent age, response rate and sampling strategies may differ. Prevalence estimates in North America are 2% to 10% while estimates in other countries are 2.7% to 12%. Currently available data suggest little geographic variability in the nature of symptoms.14 Urgency/OAB. The prevalence of OAB symptoms has been assessed in multiple large, population based studies. However, some studies identified OAB based on urinary frequency rather than urgency. Others did not discriminate between patients with urgency and those with urge urinary incontinence. Similarly the LUTS prevalence has been the subject of numerous studies but in them it is often difficult to specifically identify the subgroup with urgency symptoms. Across studies there is a lack of uniformity regarding case definition, sampling strategy, sample characteristics and response rate. With a few exceptions urgency symptoms were present in 10% to 15% of survey participants and
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symptoms occurred with similar frequency in men and women. Afferent Symptom Severity The summarized questionnaire studies suggest that a fairly significant proportion of the worldwide population has afferent urological symptoms. However, many symptoms are mild and cause minimal bother. For instance, cluster analysis showed that approximately 55% of men and women with afferent symptoms have a solitary mild symptom that causes little impact.15 Furthermore, only approximately 50% of individuals with afferent symptoms consider them bothersome.16,17 Thus, the true burden of disease is probably overstated by symptom based prevalence studies. However, examining patients with early or mild afferent symptoms may be instructive to aid in the identification of factors associated with symptom progression. Notably most research cohorts related to afferent urological conditions have been limited to patients with chronic and severe symptoms. Clinician Diagnosis IC/PBS. Female participants in NHS were asked by mailed questionnaires in 1994 and 1995 whether they had ever been diagnosed with IC (not urinary tract infection).18 Subsequent medical record reviews were done to confirm a physician diagnosis. Using these methods the IC/PBS prevalence was 52/100,000 and 67/100,000 individuals in the NHS I and II cohorts, respectively. A subsequent study was done using administrative billing data on the Kaiser Permanente Northwest managed care population in the Portland, Oregon metropolitan area.19 Patients with IC/PBS were identified by the ICD-9 code 595.1 (IC) in the electronic medical record. The prevalence of the diagnosis was found to be 197/100,000 women and 41/100,000 men. Prostatitis. A problem with data analysis based on clinician diagnoses for prostatitis is that the available ICD-9 codes 601.0 (acute prostatitis), 601.1 (CP) and 601.9 (prostatitis not otherwise specified) do not correspond to the NIH prostatitis classification scheme.20 Therefore, it is not possible to identify individuals with CP/CPPS (NIH type III prostatitis) based only on administrative billing codes. Nevertheless, such data are often available on a specific population and can provide an estimated prevalence of all prostatitis types. In Olmsted County, Minnesota, investigators selected a random sample of 2,113 men 40 to 79 years old and obtained the medical records from July 1992 through February 1996.21 The records were reviewed for any diagnosis of prostatitis and the overall prevalence was 9%. A subsequent study used administrative billing data on the Kaiser Permanente Northwest managed care
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population from May 1, 1998 to April 30, 2004 and identified a prostatitis diagnosis in 4.5% of the male population.22 OAB. The prevalence of OAB in Medicare beneficiaries was estimated using 2003 and 2004 Medicare claims data.23 Since no specific ICD-9 code exists for OAB, the condition was defined based on any of certain codes, including 596.51 (hypertonicity of bladder, hyperactivity, OAB), 596.59 (other functional disorder of bladder, detrusor instability), 788.31 (urge incontinence), 788.33 (mixed incontinence), 788.4 (frequency of urination and polyuria), 788.41 (urinary frequency) and 788.42 (polyuria). Using this definition the OAB prevalence was 8.8%. Clinical Prevalence A randomly selected group of 48 Canadian urologists completed an outpatient log for 2 weeks in 2004 to identify patients with prostatitis, IC/PBS or epididymitis.24 Of the 8,712 patients the diagnosis was prostatitis in 2.7% of the men, IC/PBS in 7.9% of the women and 0.4% of the men, and epididymitis in 0.9% of the men. Approximately 80% of patients with epididymitis reported a symptom duration of greater than 3 months. In a separate study in 28 outpatient urology practices in Italy all men between the ages of 25 and 50 years with a clinical diagnosis of CP/CPPS were prospectively identified during a 6-month period.25 A total of 764 patients were identified, including 225 with new diagnoses. This yielded a CP/CPPS 13.8% prevalence rate and a 4.5% incidence rate. Finally, a primary care practice estimated the IC/PBS prevalence by administering a screening questionnaire, followed by potassium sensitivity testing.26 They identified IC/PBS in 4.3% of their patients using these methods. In regard to OAB symptoms retrospective analysis of a primary care research database in the United Kingdom identified a documented urinary urgency symptom prevalence of 0.41/1,000 individuals, although the prevalence of any OAB symptom (frequency, nocturia, urgency or urge incontinence) was considerably higher at 3.9/1,000.27 Office Visits The National Ambulatory Medical Care Survey is an ongoing study in which patient visits from participating physicians are tabulated during a randomly selected week each year. For each selected patient visit physicians complete an encounter form detailing the specific clinical services provided during the visit as well as patient demographics and diagnoses. Data from the 1990 to 1994 surveys were used to assess the number of visits related to prostatitis.28 There were almost 2 million office visits each year
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with prostatitis listed as a diagnosis, of which 46% were to urologists and 47% were to primary care physicians. A prostatitis diagnosis was assigned at 8% and 1% of all urologist and primary care physicians visits, respectively. In the same analysis epididymo-orchitis accounted for 0.29% of ambulatory office visits in men younger than 50 years compared with 0.77% for prostatitis in the same age group. A more recent review of National Ambulatory Medical Care Survey data from 1992 to 2000 showed that combined physician outpatient and hospital outpatient visits for prostatitis had decreased slightly to 1,798/100,000 men.29 Summary Approximately 0.5% of women report a previous diagnosis of IC/PBS while 15% of men report a previous diagnosis of prostatitis. The prevalence of IC/ PBS symptoms is 1% to 2% in American women, 0.5% in European women and 2 to 3-fold lower in men. The prevalence of CP/CPPS symptoms in men is 2% to 10% worldwide. The prevalence of urinary urgency symptoms is 10% to 15% in men and women with urge urinary incontinence more common in women. Symptom based studies indicate a spectrum of symptom severity. The prevalence of clinician diagnosed afferent urological disease is 0.2% or less for IC/PBS, 5% to 10% for prostatitis and 9% for OAB. Anecdotal data and clinical experience indicate that chronic scrotal pain (orchialgia/chronic epididymitis) is a fairly common condition but data on this condition are essentially nonexistent. Disorders and symptoms related to afferent neurourology result in numerous urology office visits and comprise 10% to 15% of patients at urology clinics. There is extremely limited information on racial/ethnic variability in those with afferent urological disorders but the few groups that have investigated this issue identified no significant differences.30 –32 Although there are clearly gender differences in various afferent symptom characteristics, they are not pronounced.
AFFERENT UROLOGICAL SYMPTOM NATURAL HISTORY The natural history of a condition can be characterized by incidence, remission rate, symptom progression and symptom variability. Compared with prevalence data relatively little is known about the incidence rate of afferent urological conditions. A study of male enrollees in an American managed care health plan identified an incidence rate of 3.3/ 1,000 men per year for physician diagnosed type III prostatitis (CP/CPPS) from May 2002 to May 2004.33 Symptom duration at presentation was less
than 3 months in 44% of patients, 3 months or greater in 31% and unspecified in 25%. Most new prostatitis diagnoses were made by primary care physicians. That group also studied incident cases of IC/PBS in the same population and identified an incidence of 15/100,000 women per year.34 In contrast to CP/CPPS, most new IC/PBS cases were diagnosed by urologists. Median symptom duration at diagnosis was 1 year (range 2 weeks to 30 years). A separate study in Olmsted County, Minnesota, identified a significantly lower IC/PBS incidence rate of 1.6/100,000 women.35 The lower rate in this series may have been partly due to the earlier time point of this study (through 1996), when IC/PBS diagnostic criteria may have been more rigid. The average age of men and women with newly diagnosed IC/PBS or CP/CPPS in these studies was 45 to 53 years. Regarding new onset of symptoms a small study in 119 men without CP/CPPS symptoms showed that 4 (3%) had symptoms 1 year later.36 The incidence and remission rates of urinary incontinence have been the subject of a number of series but incidence studies focusing on OAB or urgency symptoms are rare. Sequential postal surveys of 14,802 community dwelling women in the United Kingdom identified a yearly incidence rate of 12% to 15% and a yearly remission rate of 28% to 35% for the symptom of urinary urgency.37 A postal survey of 2,284 Danish women 40 years old or older who completed a questionnaire about LUTS at baseline and 12 months later identified a 6.1% urinary urgency incidence rate and a 29% remission rate.38 Symptom progression refers to trends in symptom severity with time. For OAB symptoms it is well documented that symptom prevalence and severity increase with age.37 However, the time course of OAB symptoms in individuals is incompletely understood. For example, to my knowledge the extent to which urgency (OAB dry) progresses to urge incontinence (OAB wet) is not known. This is an area that has been more extensively studied in patients with CP/CPPS and IC/PBS. In a multi-institutional research cohort of 445 men with a median age of 42 years who had CP/CPPS and were followed with serial questionnaires at 3-month intervals 31% considered themselves moderately or markedly improved after 2 years and only 8% considered themselves worse compared to baseline.39 In a similar longitudinal multi-institutional research cohort of women with a median age of 43 years who had IC/PBS 15% to 20% had symptom improvement and 15% to 20% had worse symptoms at 12-month followup.40 In contrast, a longitudinal study in 286 male health maintenance organization enrollees with newly diagnosed CP/CPPS found that 52% had at least 50% improvement at 12 months.41 On average symptoms improved substantially during
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months 1 to 3, modestly from months 3 to 6 and remained unchanged thereafter. These findings suggest that research patients with chronic afferent symptoms have less spontaneous improvement in symptoms with time than community based patients. Symptom variability refers to short-term fluctuations that may occur during days or weeks. Symptom exacerbation (flares) is commonly reported by patients with IC/PBS and CP/CPPS and many practice elaborate self-care measures at these times (bladder instillation, medication titration etc). To date longitudinal studies related to urological pain or urgency symptoms have collected data at infrequent time points, eg every 3 months. Thus, essentially no systematic data exist on the frequency, duration and severity of symptom flares or on predictors of symptom exacerbation. Shortterm afferent symptom variability may have a significant impact on quality of life and it is clear that this aspect of afferent neurourology deserves more attention.
AFFERENT UROLOGICAL DISORDERS— PART OF A SYSTEMIC DISEASE COMPLEX? Multiple epidemiological studies have identified certain medical and psychological conditions that are more commonly present in individuals with afferent urological disorders than in age matched controls (see supplementary material). These relationships have been incompletely studied, especially for OAB. For example, to my knowledge no studies have been done to specifically determine whether allergy, back pain, noncardiac chest pain, dyspepsia, fibromyalgia or chronic headache is associated with urinary urgency/OAB. Furthermore, the significance of these associations is not clear at this time. There are individuals with afferent urological symptoms/disorders who do not manifest any associated conditions. To my knowledge the degree to which these concomitant conditions impact urological symptom severity, quality of life, natural history and response to therapy is unknown at this point but studies are under way to examine these issues (www.mappnetwork.org).
OBJECTIVE MEASUREMENT OF UROGENITAL SENSORY PERCEPTION Various objective testing measures have been described to investigate GU tract afferent function. Nonevocative testing measures include assessing bladder sensation during filling cystometry,43 measuring current perception thresholds using electrical
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stimuli delivered to pelvic structures,44 – 46 functional brain imaging during bladder filling,47 and assessing somatic responses to thermal and pressure stimuli.48 Examples of evocative sensory examinations include the potassium sensitivity test for IC/PBS49 and the intravesical ice water test.50 A comprehensive review of these measures is beyond the scope of this article.
CONCLUSIONS The term afferent neurourology can be used to describe the processing of sensory information related to the GU tract. Abnormal sensory processing in the GU tract or centrally causes pain and urinary urgency symptoms. Epidemiological studies indicate that afferent urological disorders are common worldwide with a similar prevalence rate in men and women. There is a spectrum of symptom severity and studying patients with early symptoms may help identify factors associated with symptom progression. The natural history of afferent urological symptoms is poorly understood. Particularly a better understanding of patterns and predictors of short-term symptom fluctuations is needed. Some patients with afferent urological disorders show nonurological pain conditions and they may have systemic abnormalities that contribute to the etiology of these seemingly disparate conditions. Further development of objective measures to assess urogenital sensory perceptions would be greatly useful to aid our understanding of these enigmatic conditions.
APPENDIX Afferent, efferent and structural abnormalities1,42 Sensory/Afferent Abnormalities Interstitial cystitis/painful bladder syndrome Chronic prostatitis/chronic pelvic pain syndrome Overactive bladder (dry) Urethral pain syndrome Vulval pain syndrome Vaginal pain syndrome Scrotal pain syndrome/orchialgia/chronic epididymitis Pelvic pain syndrome Motor/Efferent Abnormalities Detrusor failure Urge incontinence/detrusor overactivity Detrusor-sphincter dyssynergia Dysfunctional voiding/pseudodyssynergia Diminished bladder compliance (muscle) Structural Abnormalities Stress incontinence Pelvic prolapse Urinary fistulas Diminished bladder compliance (fibrosis/scar) Anatomical bladder outlet obstruction
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43. Lowenstein L, FitzGerald MP, Kenton K et al: Validation of a real-time urodynamic measure of urinary sensation. Am J Obstet Gynecol 2008; 198: 661.
47. Griffiths D and Tadic SD: Bladder control, urgency, and urge incontinence: evidence from functional brain imaging. Neurourol Urodyn 2008; 27: 466.
44. Kenton K, Simmons J, FitzGerald MP et al: Urethral and bladder current perception thresholds: normative data in women. J Urol 2007; 178: 189.
48. Ness TJ, Powell-Boone T, Cannon R et al: Psychosocial evidence of hypersensitivity in subjects with interstitial cystitis. J Urol 2005; 173: 1983.
45. De Laet K, De Wachter S and Wyndaele JJ: Current perception thresholds in the lower urinary tract: sine- and square-wave currents studied in young healthy volunteers. Neurourol Urodyn 2005; 24: 261.
49. Parsons CL, Zupkas P and Parsons JK: Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome. Urology 2001; 57: 428.
46. Yilmaz U, Ciol MA, Berger RE et al: Sensory perception thresholds in men with chronic pelvic pain syndrome. Urology 2010; 75: 34.
50. Mukerji G, Waters J, Chessell IP et al: Pain during ice water test distinguishes clinical bladder hypersensitivity from overactivity disorders. BMC Urol 2006; 6: 31.
Abbreviations and Acronyms CP ⫽ chronic prostatitis CPPS ⫽ chronic pelvic pain syndrome GU ⫽ genitourinary IC ⫽ interstitial cystitis LUTS ⫽ lower urinary tract symptoms NHS ⫽ Nurses’ Health Study NIH ⫽ National Institutes of Health OAB ⫽ overactive bladder PBS ⫽ painful bladder syndrome Submitted for publication September 22, 2009. * Correspondence: Department of Urology, University of Michigan Medical Center, 1500 East Medical Center Dr., Ann Arbor, Michigan 481095330 (telephone: 734-232-4881; FAX: 734-9369127; e-mail: [email protected]). Supplementary material for this article can be obtained at http://www.med.umich.edu/urology/ research/ManuscriptAppendices/index.html.
Purpose: Multiple urological conditions are characterized by bothersome sensations such as pain or urinary urgency. There is significant confusion about the etiology and pattern of these symptoms. Materials and Methods: The term afferent neurourology is introduced to describe the study of sensory processing related to the genitourinary tract. Epidemiological studies related to afferent neurourology are reviewed and unique challenges to our understanding of these disorders are described. Results: Afferent urological disorders are characterized by urological pain or urinary urgency. Conceptually these afferent disorders can be differentiated from efferent urological disorders and structural urological abnormalities. Afferent urological disorders are common in men and women, although symptom severity is variable. Study of the entire disease spectrum may provide insight into pathogenesis and prevention. The natural history of these symptoms is poorly understood. Afferent urological disorders commonly co-occur with other poorly understood somatic symptoms, suggesting that symptoms may be due to a systemic disorder in certain individuals. Mechanisms responsible for these sensory abnormalities are poorly understood and may arise from central and peripheral abnormalities. Conclusions: Urinary pain and urgency are common, bothersome symptoms that are currently understood poorly and managed ineffectively. Intentional recognition of sensory urological abnormalities as a separate field of study may enhance research efforts into these conditions and improve treatment outcomes. Key Words: urinary bladder; cystitis, interstitial; pain; prostatitis; epidemiology
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NEUROUROLOGY encompasses the study of lower urinary tract neurophysiology and the functional urological abnormalities that result from neurological dysfunction, disease or injury. Multiple neurological disorders can adversely affect urinary tract function. Management principles focus on preserving continence and preventing upper urinary tract complications by decreasing detrusor overactivity and maintaining low bladder storage pressure. Therefore, the focus is on identifying and treating abnormal motor (efferent) neurological activity.
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0022-5347/10/1842-0432/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
A Novel Paradigm A different type of abnormality exists in which bothersome sensations of pain or urinary urgency are the defining complaints. For these conditions the concept of afferent neurourology has been introduced.1 This term refers to the field of study concerned with the processing of sensory information related to the GU tract. This review expands on this concept to discuss specific epidemiological data that are relevant to the field of afferent
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RESEARCH, INC.
Vol. 184, 432-439, August 2010 Printed in U.S.A. DOI:10.1016/j.juro.2010.04.012
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neurourology. This information may focus attention and research on this poorly understood field. Defining Characteristics of Disorders The abnormal processing of sensory information that characterizes afferent neurourology results in pain and urinary urgency symptoms. Pain may be described by patients as pressure or discomfort but such symptoms still meet the accepted definition of pain, that is an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage.2 Urinary frequency and nocturia are often but not always present. However, frequency and nocturia are behaviors, rather than sensory experiences, that are caused by urinary urgency, pain and many other factors, such as fluid intake, medical conditions, medication etc. Therefore, frequency and nocturia are not considered defining characteristics in the afferent neurourology paradigm. Clinical Syndromes Urological pain and urgency result in clinically recognized conditions such as IC/PBS, CP/CPPS, OAB, LUTS, chronic epididymitis and orchialgia. Each is a syndrome (collection of symptoms) without objective markers. It is common for individuals to have symptoms that meet the criteria for more than 1 of these conditions. OAB can be subcategorized into OAB dry (urgency without urge incontinence) and OAB wet (urgency with urge incontinence). These 2 subgroups are typically considered part of an OAB disease spectrum but to my knowledge it is unknown whether they in fact share the same underlying pathophysiology. It is also unclear to what extent those with OAB dry progress to OAB wet. Furthermore, the mechanism responsible for converting the afferent symptom of urgency to the efferent symptom of urge incontinence is not well understood. Afferent symptoms and disorders can be differentiated from efferent abnormalities (eg detrusor failure, decreased bladder compliance and detrusor overactivity) and structural abnormalities (eg stress incontinence, prolapse and anatomical bladder outlet obstruction) (see Appendix). Efferent and structural abnormalities tend to be better understood because each has an objective diagnostic test that can be done to confirm the diagnosis and quantify severity. Conversely the lack of objective markers for afferent disorders has hampered our ability to confirm the diagnosis, identify patient subgroups or provide prognostic information. Furthermore, multiple afferent, efferent and structural disorders may be present in an individual.
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LOWER URINARY TRACT SYMPTOMS Traditionally the term LUTS has referred to symptoms attributable to benign prostatic hyperplasia. However, there is growing recognition that a more expansive underlying pathophysiology than the prostate alone is responsible for these symptoms.3 For example, LUTS are equally common in men and women.4 The LUTS concept combines various symptoms that are typically subcategorized as voiding symptoms (incomplete bladder emptying, intermittence, slow stream and straining to void) and storage symptoms (frequency, urgency and nocturia). This concept is fairly comprehensive of common urological symptoms and LUTS symptoms are commonly quantified and used to measure symptom severity. However, the LUTS paradigm ignores pain, which is often present in patients with LUTS.5,6 Furthermore, subcategorization into voiding and storage symptoms implicitly acknowledges the disparate nature of these symptom types. Thus, 2 patients with the same degree of LUTS based on a symptom score may show completely different symptom characteristics. Also, the more specific subcategory of storage symptoms includes a symptom (urgency) and behaviors (frequency and nocturia) that may be completely unrelated, as explained. In the afferent neurourology paradigm urgency and pain symptoms are isolated as unique sensory abnormalities.
AFFERENT UROLOGICAL DISORDER PREVALENCE Generally prevalence studies of afferent urological disorders have been done in 1 of 5 ways. Collectively an impression about the overall prevalence of these conditions can be formed. 1) Surveys have been done that ask participants whether they have ever been diagnosed with a condition of interest (self-report studies). Such studies are subject to recall bias and depend on accurate clinical diagnoses being communicated to patients. 2) Questionnaires have been administered to identify symptoms suggestive of the condition of interest (symptom assessments). These studies are often subject to response bias since individuals with the symptoms may be more likely to complete the questionnaire. Also, identifying symptoms is not the same as diagnosing a specific medical condition, and to our knowledge the sensitivity and specificity of various questionnaire definitions for these conditions are unknown. 3) Administrative billing data have been used to identify individuals in a population with a specific diagnosis indicating an afferent urological disorder (clinician diagnosis). These studies require an accurate clinician diagnosis and are limited by the categorization schemes that are inclusive in billing data. 4) Clinical records
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have been reviewed to identify the number of patients seen with certain diagnoses (clinical prevalence). These studies estimate disease prevalence in a clinical population but do not provide a true population prevalence estimate. 5) Office visits for a particular condition have been counted to estimate disease prevalence (office visits). Data in these studies tend to be fairly reliable since they are obtained directly from caregivers soon after the office visit. However, these studies are limited to clinical patients and do not identify individuals with the conditions. Instead they count the total number of office visits for a particular condition. Also, the sampling time frame is short. Thus, this type of study may not generate reliable data for medical diagnoses that are fairly uncommon. Self-Report Studies Two large-scale studies in the United States have used self-report to estimate the IC/PBS prevalence.7 The first study was done as part of the 1989 National Health Interview Survey and the second was part of the National Health and Nutrition Examination Survey III, done between 1988 and 1994. The same definition of IC/PBS was used in each. Participants were asked, “Have you ever had symptoms of a bladder infection (such as pain in your bladder and frequent urination) that lasted more than 3 months?” Those who gave a positive response were then asked, “When you had this condition, were you told that you had interstitial cystitis or painful bladder syndrome?” An affirmative answer to the 2 questions was considered to define IC/ PBS. Prevalence estimates obtained from these 2 studies were virtually identical. In the National Health Interview Survey the overall prevalence was 500/100,000 population and the prevalence in women was 865/100,000. In the National Health and Nutrition Examination Survey III the prevalence was 470/100,000 population, including 60/100,000 men and 850/100,000 women. This equals approximately 83,000 men and 1.2 million women in the United States. Four population based self-report studies of prostatitis have been done. A total of 31,681 male participants in the United States Health Professionals Follow-Up Study in 1992 were asked, “Have you ever had prostatitis or a prostatic infection?”8 A positive response was obtained in 16% of respondents. A study in 1,832 men in Finland inquired about a previous diagnosis of prostatitis and identified a 14.2% prevalence rate.9 Based on questionnaires administered to 703 black American men as part of the Flint Men’s Health Study 6.7% reported a history of physician diagnosed prostatitis.10 Finally, a survey of 184 members of a United States National Guard Unit comprising 20 to 49-
year-old men identified 5% with self-reported prostatitis.11 Based on concerns about industrial exposure and the risk of epididymitis in 1992 a survey of 1,342 male textile workers was done.12 Of respondents 11.1% reported having had testicular pain severe enough to consult a physician, 6.4% reported a history of epididymitis and 1.3% reported a history of orchitis. No additional clinical data were obtained to differentiate acute from chronic complaints. To my knowledge no self-report prevalence studies of OAB have been done to date. Symptoms (see supplementary material) IC/PBS. Multiple population based studies have estimated the prevalence of IC/PBS symptoms. Since the studies used different case definitions, it is difficult to make comparisons across them. Also, sampling strategies and response rates varied considerably. The prevalence estimate in Europe is approximately 0.5% in women while in the United States it is 1% to 11% with most estimates in the 1% to 2% range. The prevalence in men is typically 2 to 3-fold less than in women. Prostatitis. Numerous prevalence studies have also been done to identify prostatitis-like symptoms. Unlike similar studies of IC/PBS, many prostatitis studies have used a standard definition to identify symptoms. As originally proposed by Nickel et al,13 this definition uses responses from the NIH CP Symptom Index to define prostatitis symptoms as perineal or ejaculatory pain plus a score of 4 or greater on the NIH CP Symptom Index pain subscale. Using a standard definition permits better comparisons across various studies, although other factors such as respondent age, response rate and sampling strategies may differ. Prevalence estimates in North America are 2% to 10% while estimates in other countries are 2.7% to 12%. Currently available data suggest little geographic variability in the nature of symptoms.14 Urgency/OAB. The prevalence of OAB symptoms has been assessed in multiple large, population based studies. However, some studies identified OAB based on urinary frequency rather than urgency. Others did not discriminate between patients with urgency and those with urge urinary incontinence. Similarly the LUTS prevalence has been the subject of numerous studies but in them it is often difficult to specifically identify the subgroup with urgency symptoms. Across studies there is a lack of uniformity regarding case definition, sampling strategy, sample characteristics and response rate. With a few exceptions urgency symptoms were present in 10% to 15% of survey participants and
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symptoms occurred with similar frequency in men and women. Afferent Symptom Severity The summarized questionnaire studies suggest that a fairly significant proportion of the worldwide population has afferent urological symptoms. However, many symptoms are mild and cause minimal bother. For instance, cluster analysis showed that approximately 55% of men and women with afferent symptoms have a solitary mild symptom that causes little impact.15 Furthermore, only approximately 50% of individuals with afferent symptoms consider them bothersome.16,17 Thus, the true burden of disease is probably overstated by symptom based prevalence studies. However, examining patients with early or mild afferent symptoms may be instructive to aid in the identification of factors associated with symptom progression. Notably most research cohorts related to afferent urological conditions have been limited to patients with chronic and severe symptoms. Clinician Diagnosis IC/PBS. Female participants in NHS were asked by mailed questionnaires in 1994 and 1995 whether they had ever been diagnosed with IC (not urinary tract infection).18 Subsequent medical record reviews were done to confirm a physician diagnosis. Using these methods the IC/PBS prevalence was 52/100,000 and 67/100,000 individuals in the NHS I and II cohorts, respectively. A subsequent study was done using administrative billing data on the Kaiser Permanente Northwest managed care population in the Portland, Oregon metropolitan area.19 Patients with IC/PBS were identified by the ICD-9 code 595.1 (IC) in the electronic medical record. The prevalence of the diagnosis was found to be 197/100,000 women and 41/100,000 men. Prostatitis. A problem with data analysis based on clinician diagnoses for prostatitis is that the available ICD-9 codes 601.0 (acute prostatitis), 601.1 (CP) and 601.9 (prostatitis not otherwise specified) do not correspond to the NIH prostatitis classification scheme.20 Therefore, it is not possible to identify individuals with CP/CPPS (NIH type III prostatitis) based only on administrative billing codes. Nevertheless, such data are often available on a specific population and can provide an estimated prevalence of all prostatitis types. In Olmsted County, Minnesota, investigators selected a random sample of 2,113 men 40 to 79 years old and obtained the medical records from July 1992 through February 1996.21 The records were reviewed for any diagnosis of prostatitis and the overall prevalence was 9%. A subsequent study used administrative billing data on the Kaiser Permanente Northwest managed care
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population from May 1, 1998 to April 30, 2004 and identified a prostatitis diagnosis in 4.5% of the male population.22 OAB. The prevalence of OAB in Medicare beneficiaries was estimated using 2003 and 2004 Medicare claims data.23 Since no specific ICD-9 code exists for OAB, the condition was defined based on any of certain codes, including 596.51 (hypertonicity of bladder, hyperactivity, OAB), 596.59 (other functional disorder of bladder, detrusor instability), 788.31 (urge incontinence), 788.33 (mixed incontinence), 788.4 (frequency of urination and polyuria), 788.41 (urinary frequency) and 788.42 (polyuria). Using this definition the OAB prevalence was 8.8%. Clinical Prevalence A randomly selected group of 48 Canadian urologists completed an outpatient log for 2 weeks in 2004 to identify patients with prostatitis, IC/PBS or epididymitis.24 Of the 8,712 patients the diagnosis was prostatitis in 2.7% of the men, IC/PBS in 7.9% of the women and 0.4% of the men, and epididymitis in 0.9% of the men. Approximately 80% of patients with epididymitis reported a symptom duration of greater than 3 months. In a separate study in 28 outpatient urology practices in Italy all men between the ages of 25 and 50 years with a clinical diagnosis of CP/CPPS were prospectively identified during a 6-month period.25 A total of 764 patients were identified, including 225 with new diagnoses. This yielded a CP/CPPS 13.8% prevalence rate and a 4.5% incidence rate. Finally, a primary care practice estimated the IC/PBS prevalence by administering a screening questionnaire, followed by potassium sensitivity testing.26 They identified IC/PBS in 4.3% of their patients using these methods. In regard to OAB symptoms retrospective analysis of a primary care research database in the United Kingdom identified a documented urinary urgency symptom prevalence of 0.41/1,000 individuals, although the prevalence of any OAB symptom (frequency, nocturia, urgency or urge incontinence) was considerably higher at 3.9/1,000.27 Office Visits The National Ambulatory Medical Care Survey is an ongoing study in which patient visits from participating physicians are tabulated during a randomly selected week each year. For each selected patient visit physicians complete an encounter form detailing the specific clinical services provided during the visit as well as patient demographics and diagnoses. Data from the 1990 to 1994 surveys were used to assess the number of visits related to prostatitis.28 There were almost 2 million office visits each year
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with prostatitis listed as a diagnosis, of which 46% were to urologists and 47% were to primary care physicians. A prostatitis diagnosis was assigned at 8% and 1% of all urologist and primary care physicians visits, respectively. In the same analysis epididymo-orchitis accounted for 0.29% of ambulatory office visits in men younger than 50 years compared with 0.77% for prostatitis in the same age group. A more recent review of National Ambulatory Medical Care Survey data from 1992 to 2000 showed that combined physician outpatient and hospital outpatient visits for prostatitis had decreased slightly to 1,798/100,000 men.29 Summary Approximately 0.5% of women report a previous diagnosis of IC/PBS while 15% of men report a previous diagnosis of prostatitis. The prevalence of IC/ PBS symptoms is 1% to 2% in American women, 0.5% in European women and 2 to 3-fold lower in men. The prevalence of CP/CPPS symptoms in men is 2% to 10% worldwide. The prevalence of urinary urgency symptoms is 10% to 15% in men and women with urge urinary incontinence more common in women. Symptom based studies indicate a spectrum of symptom severity. The prevalence of clinician diagnosed afferent urological disease is 0.2% or less for IC/PBS, 5% to 10% for prostatitis and 9% for OAB. Anecdotal data and clinical experience indicate that chronic scrotal pain (orchialgia/chronic epididymitis) is a fairly common condition but data on this condition are essentially nonexistent. Disorders and symptoms related to afferent neurourology result in numerous urology office visits and comprise 10% to 15% of patients at urology clinics. There is extremely limited information on racial/ethnic variability in those with afferent urological disorders but the few groups that have investigated this issue identified no significant differences.30 –32 Although there are clearly gender differences in various afferent symptom characteristics, they are not pronounced.
AFFERENT UROLOGICAL SYMPTOM NATURAL HISTORY The natural history of a condition can be characterized by incidence, remission rate, symptom progression and symptom variability. Compared with prevalence data relatively little is known about the incidence rate of afferent urological conditions. A study of male enrollees in an American managed care health plan identified an incidence rate of 3.3/ 1,000 men per year for physician diagnosed type III prostatitis (CP/CPPS) from May 2002 to May 2004.33 Symptom duration at presentation was less
than 3 months in 44% of patients, 3 months or greater in 31% and unspecified in 25%. Most new prostatitis diagnoses were made by primary care physicians. That group also studied incident cases of IC/PBS in the same population and identified an incidence of 15/100,000 women per year.34 In contrast to CP/CPPS, most new IC/PBS cases were diagnosed by urologists. Median symptom duration at diagnosis was 1 year (range 2 weeks to 30 years). A separate study in Olmsted County, Minnesota, identified a significantly lower IC/PBS incidence rate of 1.6/100,000 women.35 The lower rate in this series may have been partly due to the earlier time point of this study (through 1996), when IC/PBS diagnostic criteria may have been more rigid. The average age of men and women with newly diagnosed IC/PBS or CP/CPPS in these studies was 45 to 53 years. Regarding new onset of symptoms a small study in 119 men without CP/CPPS symptoms showed that 4 (3%) had symptoms 1 year later.36 The incidence and remission rates of urinary incontinence have been the subject of a number of series but incidence studies focusing on OAB or urgency symptoms are rare. Sequential postal surveys of 14,802 community dwelling women in the United Kingdom identified a yearly incidence rate of 12% to 15% and a yearly remission rate of 28% to 35% for the symptom of urinary urgency.37 A postal survey of 2,284 Danish women 40 years old or older who completed a questionnaire about LUTS at baseline and 12 months later identified a 6.1% urinary urgency incidence rate and a 29% remission rate.38 Symptom progression refers to trends in symptom severity with time. For OAB symptoms it is well documented that symptom prevalence and severity increase with age.37 However, the time course of OAB symptoms in individuals is incompletely understood. For example, to my knowledge the extent to which urgency (OAB dry) progresses to urge incontinence (OAB wet) is not known. This is an area that has been more extensively studied in patients with CP/CPPS and IC/PBS. In a multi-institutional research cohort of 445 men with a median age of 42 years who had CP/CPPS and were followed with serial questionnaires at 3-month intervals 31% considered themselves moderately or markedly improved after 2 years and only 8% considered themselves worse compared to baseline.39 In a similar longitudinal multi-institutional research cohort of women with a median age of 43 years who had IC/PBS 15% to 20% had symptom improvement and 15% to 20% had worse symptoms at 12-month followup.40 In contrast, a longitudinal study in 286 male health maintenance organization enrollees with newly diagnosed CP/CPPS found that 52% had at least 50% improvement at 12 months.41 On average symptoms improved substantially during
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months 1 to 3, modestly from months 3 to 6 and remained unchanged thereafter. These findings suggest that research patients with chronic afferent symptoms have less spontaneous improvement in symptoms with time than community based patients. Symptom variability refers to short-term fluctuations that may occur during days or weeks. Symptom exacerbation (flares) is commonly reported by patients with IC/PBS and CP/CPPS and many practice elaborate self-care measures at these times (bladder instillation, medication titration etc). To date longitudinal studies related to urological pain or urgency symptoms have collected data at infrequent time points, eg every 3 months. Thus, essentially no systematic data exist on the frequency, duration and severity of symptom flares or on predictors of symptom exacerbation. Shortterm afferent symptom variability may have a significant impact on quality of life and it is clear that this aspect of afferent neurourology deserves more attention.
AFFERENT UROLOGICAL DISORDERS— PART OF A SYSTEMIC DISEASE COMPLEX? Multiple epidemiological studies have identified certain medical and psychological conditions that are more commonly present in individuals with afferent urological disorders than in age matched controls (see supplementary material). These relationships have been incompletely studied, especially for OAB. For example, to my knowledge no studies have been done to specifically determine whether allergy, back pain, noncardiac chest pain, dyspepsia, fibromyalgia or chronic headache is associated with urinary urgency/OAB. Furthermore, the significance of these associations is not clear at this time. There are individuals with afferent urological symptoms/disorders who do not manifest any associated conditions. To my knowledge the degree to which these concomitant conditions impact urological symptom severity, quality of life, natural history and response to therapy is unknown at this point but studies are under way to examine these issues (www.mappnetwork.org).
OBJECTIVE MEASUREMENT OF UROGENITAL SENSORY PERCEPTION Various objective testing measures have been described to investigate GU tract afferent function. Nonevocative testing measures include assessing bladder sensation during filling cystometry,43 measuring current perception thresholds using electrical
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stimuli delivered to pelvic structures,44 – 46 functional brain imaging during bladder filling,47 and assessing somatic responses to thermal and pressure stimuli.48 Examples of evocative sensory examinations include the potassium sensitivity test for IC/PBS49 and the intravesical ice water test.50 A comprehensive review of these measures is beyond the scope of this article.
CONCLUSIONS The term afferent neurourology can be used to describe the processing of sensory information related to the GU tract. Abnormal sensory processing in the GU tract or centrally causes pain and urinary urgency symptoms. Epidemiological studies indicate that afferent urological disorders are common worldwide with a similar prevalence rate in men and women. There is a spectrum of symptom severity and studying patients with early symptoms may help identify factors associated with symptom progression. The natural history of afferent urological symptoms is poorly understood. Particularly a better understanding of patterns and predictors of short-term symptom fluctuations is needed. Some patients with afferent urological disorders show nonurological pain conditions and they may have systemic abnormalities that contribute to the etiology of these seemingly disparate conditions. Further development of objective measures to assess urogenital sensory perceptions would be greatly useful to aid our understanding of these enigmatic conditions.
APPENDIX Afferent, efferent and structural abnormalities1,42 Sensory/Afferent Abnormalities Interstitial cystitis/painful bladder syndrome Chronic prostatitis/chronic pelvic pain syndrome Overactive bladder (dry) Urethral pain syndrome Vulval pain syndrome Vaginal pain syndrome Scrotal pain syndrome/orchialgia/chronic epididymitis Pelvic pain syndrome Motor/Efferent Abnormalities Detrusor failure Urge incontinence/detrusor overactivity Detrusor-sphincter dyssynergia Dysfunctional voiding/pseudodyssynergia Diminished bladder compliance (muscle) Structural Abnormalities Stress incontinence Pelvic prolapse Urinary fistulas Diminished bladder compliance (fibrosis/scar) Anatomical bladder outlet obstruction
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