Chapter Outline
Management of Interstitial Cystitis/Bladder Pain Syndrome
Hypersensitivity or sensory disorders of the lower urinary tract in women have been poorly elucidated, and management has been guided by anecdotal evidence. Reliable and standardized testing to make an accurate diagnosis remains elusive. These disorders represent a spectrum of symptoms and conditions that include chronic bacterial cystitis, urgency and frequency syndrome, “sensory urgency,” and urethral syndrome. The International Continence Society (ICS) recognizes this syndrome as genitourinary pain syndromes and syndromes suggestive of pelvic floor dysfunction. Pain is the major complaint but concomitant complaints are of the lower urinary tract, bowel, and vagina, and of a sexual or gynecologic nature. This definition includes the following syndromes: bladder pain, urethral pain, vulvar pain, vaginal pain, perineal pain, and pelvic pain. Ultimately, hypersensitivity disorders, pelvic pain syndrome, and interstitial cystitis (IC) remain diagnoses of exclusion ( ). This chapter focuses on what may be the ultimate expression of this disease process: interstitial cystitis/bladder pain syndrome.
Anatomically, the short female urethra lends itself to infectious invasion. Childbirth and sexual activity cause displacement and trauma to the bladder neck. The postmenopausal state subjects the female lower urinary tract to the effects of chronic estrogen deprivation. This leads to ischemia, with a decrease in the urethral mucosal cushion and increased susceptibility of the bladder to bacterial adherence. The result is potential exposure of the neurovascular elements of the bladder wall to urinary toxins and infectious agents. The physiologic ramifications of chronic overstimulation of the sensory nerve components of the lower urinary tract are not clearly understood.
Hypersensitivity disorders reside in most physicians’ practices. An estimated 15% of the 7 million women who experience a urinary tract infection (UTI) annually will have recurrences (greater than two episodes in 6 months or greater than three in 1 year). Of the 8.5 million women with urinary incontinence, about 40% have detrusor overactivity. More than 750,000 women have IC, and their quality of life is often lower than that of age-matched patients on renal dialysis. Significant clinical depression is present in 68% of these patients. In the absence of infection, patients with frequency, urgency, and pain are often classified as having one or more of the following: bladder pain syndrome, urethral syndrome, frequency and urgency syndrome, urethral instability, “sensory urgency,” or IC. These terms may represent one disease process in different phases or degrees of severity ( Fig. 36.1 ).
Interstitial Cystitis
IC is the most challenging and encompassing hypersensitivity disorder. Tremendous efforts have been made to gain an understanding of this disease, but the etiology remains unclear. This section presents the current understanding of the nomenclature, pathogenesis, and diagnostic approach to IC.
Nomenclature
In 1987, for research purposes, the National Institutes of Health (NIH) established standardized diagnostic criteria for IC ( Box 36.1 ). The National Interstitial Cystitis Database (NICDB), a cooperative multicenter longitudinal observation study group established in 1991, was sponsored to study the natural history of the disease and was based on a large population with symptoms consistent with IC. In 1999, the NICDB reported that the NIH guidelines were too restrictive to be used by clinicians. If the initial criteria were used, up to 60% of symptomatic women would not be diagnosed.
Category A: At least one of the following findings on cystoscopy
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Diffuse glomerulations (at least 10 per quadrant) in at least three quadrants of the bladder
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A classic Hunner ulcer
Category B: At least one of the following symptoms
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Pain associated with the bladder
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Urinary urgency
Exclusion criteria
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Age <18 years ∗
∗ Relative exclusion criteria.
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Urinary frequency while awake <8 times per day
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Nocturia fewer than two times per night
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Maximal bladder capacity >350 mL while patient is awake
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Absence of an intense urge to void with bladder filled to 150 mL of water with medium filling rate (30-100 mL/min) during cystometry
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Involuntary bladder contractions on cystometry using medium filling rate
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Duration of symptoms <9 months ∗
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Symptoms relieved by antimicrobial agents (antibiotics, urinary antiseptics), anticholinergics, or antispasmodics ∗
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Urinary tract or prostatic infection in the past 3 months ∗
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Active genital herpes
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Vaginitis ∗
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Uterine, cervical, vaginal, or urethral cancer within the past 5 years ∗
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Bladder or ureteral calculi ∗
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Urethral diverticulum ∗
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History of cyclophosphamide or chemical cystitis or tuberculosis or radiation cystitis
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Benign or malignant bladder tumors
Note: These are the original criteria and are changing.
In 2002, the ICS focused on bladder pain and introduced the term painful bladder syndrome (PBS). Defined as the complaint of suprapubic pain related to bladder filling accompanied by other symptoms, such as increased daytime and nighttime frequency, in the absence of proven urinary infection or other obvious pathology. The ICS believes this to be a preferable term to “interstitial cystitis.” Interstitial cystitis is a specific diagnosis and requires confirmation by typical cystoscopic and histological features ( ). Further study with this new terminology suggested a decreased sensitivity for diagnosis ( ).
In 2008, the European Society for the Study of Interstitial Cystitis (ESSIC) reached a consensus to rename IC and PBS to bladder pain syndrome (BPS) ( ). BPS would be diagnosed on the basis of chronic pelvic pain, pressure, or discomfort perceived to be related to the urinary bladder accompanied by at least one other urinary symptom, such as persistent urge to void or urinary frequency for greater than 6 months. Classification of BPS types might be performed according to findings at cystoscopy with hydrodistention and morphologic findings in bladder biopsies ( Box 36.2 ). Confusable diseases as the cause of the symptoms must be excluded. The presence of other organ symptoms, as well as cognitive, behavioral, emotional, and sexual symptoms, should be addressed ( Table 36.1 ) ( ). The theory behind the name change theorizes that IC reflects more on bladder symptoms and inflammation, whereas BPS falls under the taxonomic umbrella of chronic pelvic pain syndrome, which follows the 2007 Guidelines on Chronic Pelvic Pain issued by the European Association of Urology ( ).
BPS, bladder pain syndrome; ESSIC, European Society for the Study of Interstitial Cystitis; IC, Interstitial cystitis.
| Confusable Disease | Excluded or Diagnosed by |
|---|---|
| Carcinoma and carcinoma in situ | Cystoscopy and biopsy |
| Infection with | |
| Common intestinal bacteria | Routine bacterial culture |
| Chlamydia trachomatis , Ureaplasma urealyticum, | Special cultures |
| Mycoplasma hominis , Mycoplasma genitalium, | |
| Corynebacterium urealyticum , Candida species | |
| Mycobacterium tuberculosis | Dipstick, if sterile pyuria, culture for M. tuberculosis |
| Herpes simplex and human papillomavirus | Physical examination, culture |
| Radiation | Medical history |
| Chemotherapy, including immunotherapy with cyclophosphamide | Medical history |
| Anti-inflammatory therapy with tiaprofenic acid | Medical history |
| Bladder-neck obstruction and neurogenic outlet obstruction | Uroflowmetry and ultrasound |
| Bladder stone | Imaging or cystoscopy |
| Lower ureteric stone | Medical history and/or hematuria: upper urinary tract imaging such as CT or IVP |
| Urethral diverticulum | Medical history, physical examination, MRI |
| Urogenital prolapse | Medical history, physical examination |
| Endometriosis | Medical history, physical examination |
| Vaginal candidiasis | Medical history, physical examination |
| Cervical, uterine, and ovarian cancer | Physical examination, biopsies |
| Incomplete bladder emptying (retention) | Postvoid residual urine volume measured by ultrasound scanning |
| Overactive bladder | Medical history and urodynamics |
| Prostate cancer | Physical examination, PSA |
| Benign prostatic obstruction | Uroflowmetry, pressure-flow studies |
| Chronic bacterial prostatitis | Medical history, physical examination, culture |
| Chronic nonbacterial prostatitis | Medical history, physical examination, culture |
| Pudendal nerve entrapment | Medical history, physical examination, nerve block may help prove diagnosis |
| Pelvic floor muscle-related pain | Medical history, physical examination |
The definition widely used in a clinical setting is that put forth by the Society for Urodynamics and Female Urology: “An unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes” ( ). This definition is preferred because it allows treatment to begin after a relatively short symptomatic period, minimizing the delay in initiation of treatment, which could occur with definitions that require longer symptom duration (i.e. 6 months). Definitions used in research or clinical trials should be avoided in clinical practice; many patients may be misdiagnosed or have delays in diagnosis and treatment if these criteria are used.
Epidemiology
Skene first suggested the term “interstitial cystitis” in 1887. In 1907, Nitze described a painful bladder condition associated with urinary frequency and bladder ulcerations. In 1915, Hunner reported the classic ulcer associated with a contracted fibrotic bladder, mucosal congestion adjacent to the ulcers, and hemorrhage after bladder hydrodistention. Although IC was described early in the century, it was not until the 1970s that epidemiologic studies were done to evaluate and characterize this disease.
The prevalence of IC/BPS was generally estimated to be lower than 0.1%, the diagnostic criteria used previously have been found to be overly rigorous. Currently, the prevalence of IC/BPS is known to be higher than 0.1%, ranging between 0.45% ( ) and 12.6% ( ) depending on methodological factors, including the index or scale used for diagnosis. The prevalence of IC/BPS also has been reported to be twice as high in women as men in past studies ( ).
Etiology
The etiology of IC is currently unknown. Most authors believe it is multifactorial. Currently proposed causes include infectious agents, quantitative glycosaminoglycan (GAG) layer deficiency, ultrastructural abnormality of the lamina propria or interstitium of the bladder, mast cells, and neurogenic inflammation. The development and complete characterization of a promising urinary marker, antiproliferative factor may aid in our understanding of the etiology, diagnosis, and management of IC.
Infectious Agents
Extensive efforts have been made, with limited success, to establish an infectious agent as the cause of IC. first suggested a hematogenously disseminated bacterial cystitis as the cause. Most patients with IC report a history of UTI and have received several courses of antibiotics based on their symptoms, not on positive urine cultures. To date, no single bacterium, virus, fungus, or fastidious microorganism has been isolated as an etiologic factor in IC.
Some authors believe that a low bacterial count, bacterial antigens, or byproducts, such as endotoxins or P-fimbriae, may be involved. These substances can activate an autoimmune response or cause sensory nerve stimulation, thus activating the neurogenic inflammation model of IC. DNA sequencing of bladder biopsies searching for bacteria or their byproducts has demonstrated controversial results.
Gag Layer Deficiency
The concept of a defective urothelium resulting from a quantitative deficiency of its surface coat of GAGs, and thereby allowing access of a toxic urothelial substance into the interstitium of the bladder, was once the leading theory of the pathogenesis of IC. Current research is focusing on biochemical and ultrastructural studies of the surface layer of urothelium, of the umbrella cells, and intra-adhesion molecules. This may provide a more comprehensive understanding of the pathogenesis of IC.
Ultrastructural Abnormalities
Ultrastructural studies of bladder biopsy specimens after hydrodistention have revealed several distinct features. Abnormalities are observed in all tissue components of the bladder wall, including tissue cells, interstitial tissue, blood vessels, and intrinsic nerves. These features include urothelium with disrupted permeability barrier and accelerated turnover, abnormal profiles of detrusor muscle cells, and damage of intrinsic nerves and blood vessel walls. Significant fluid engorgement, with diffuse or loculated edema of tissue cells and extracellular tissue, is also seen. Lymphocytes are the predominant component, distributed unevenly throughout the tissue. Activated mast cells are readily identified adjacent to intrinsic nerves, but they are less commonly seen near blood vessels and in the suburothelium. These distinctive features are most prominent and extensive in biopsies from areas of glomerulations (submucosal hemorrhages) after diagnostic hydrodistention. These features, although recognizable, are less dramatic in severity and extent of distribution in biopsies from cystoscopically normal-appearing areas of the bladder lining. Further research has identified that urine from IC patients has a decreased level of heparin-binding epidermal growth-like factor (HB-EGF) and an increase in a putative antiproliferative factor. HB-EGF has been shown to increase toward normal values with hydrodistention. Antiproliferative factor and HB-EGF normalize after sacral neuromodulation. The abnormality in epithelial permeability/transitional dysfunction led to the development of the potassium sensitivity test.
Mast Cells
Mast cells examined ultrastructurally in IC are intimately associated with nerve fibers and terminals in the suburothelium and are found in the interstitium of the detrusor, often next to nerves and blood vessels. Mast cells are essential for the development of allergic hypersensitivity reactions. Their activation and subsequent degranulation trigger the secretion of many biologically active chemicals. These substances include histamine, serotonin, cytokines, neuropeptides (substance P), and vasoactive intestinal peptide. These mediators, especially histamine, play a role in stimulating reactions, such as vasodilation, leukocyte infiltration, and angiogenesis.
An elevated mast cell count in the bladder muscularis has been promoted as a diagnostic histopathologic feature of IC, and detrusor mastocytosis has been advocated as a more appropriate name for IC. Different values for mast cell counts in the detrusor layer have been proposed as a diagnostic marker. These values and their validity are debated. Detrusor mastocytosis has been found in 20% to 65% of patients with IC; patients with classic ulcer-type or late-stage IC have demonstrated an even higher percentage. Recently, investigators have attempted to compare the ratio of detrusor to mucosal mast cells and the relationship of nerve fibers to mast cells. The ultrastructure of the mast cell, demonstrated by electron microscopy, has shown the proximity of nerves and activated mast cells. Researchers are investigating mast cell activation and the subsequent mediator release as an origin of some of the symptoms and cystoscopic findings seen with IC. Current research involving the role of mast cells in IC has brought forth three findings: (1) the intimate association and interaction of mast cells with intrinsic nerves in the bladder wall; (2) the unlikeliness, if not incompatibility, of an immunologic pathogenetic mechanism of immunoglobulin E-mediated immediate hypersensitivity; and (3) the relationship of stress and female hormones to IC.
Neurogenic Inflammation
Neurogenic inflammation may provide the nidus for induction, establishment, and chronicity of the various tissue changes seen in IC. Other conditions in which neurogenic inflammation may be implicated include irritable bowel syndrome, vulvodynia, migraines, fibromyalgia, and multiple sclerosis. Mast cells are located in close proximity to the peripheral and central nervous systems. In addition, an intimate association between mast cells and sensory nerve fibers has been demonstrated in the integumentary, pulmonary, and gastrointestinal systems.
Excitation of sensory nerves, especially small pain C-fibers, triggers an inflammatory process through release of neuropeptides (substance P) and calcitonin gene-related peptide. Substance P causes vasodilation and increased vasopermeability and activates mast cells, causing injury with increased permeability of epithelial surfaces. Multiple events or factors trigger neurogenic inflammation. These include (1) bacterial cystitis or the antigen from the organism; (2) an increased level of estrogen; (3) toxins of endogenous and exogenous origin, including drugs, their metabolites, and certain foods; and (4) a potent mediator, such as the histamine released by activated mast cells. As our understanding of neurogenic inflammation and the role of mast cell activation progresses ( Fig. 36.2 ), the diagnosis and treatment of IC will evolve.
Diagnosis
IC/BPS is a diagnosis of exclusion. The American Urologic Association established an evidence-based clinical framework for diagnosis and overall management of IC/BPS ( Fig. 36.3 ) ( ). The guidelines state that insufficient literature was identified to constitute an evidence base for diagnosis of IC/BPS in clinical practice. For this reason, diagnosis statements are based on clinical principles or expert opinion.
History
The basic assessment should include a careful history, physical examination, and laboratory examination to document symptoms and signs that characterize IC/BPS and exclude other disorders commonly associated with IC/BPS in the differential diagnosis ( ). Patients cannot have evidence of cystitis caused by infection, use of cyclophosphamide or other chemical agents, radiation, or tuberculosis. Other infections, such as vaginitis, urethritis, urethral ureaplasma, or genital herpes, cannot be present. Also, urethral diverticulum, bladder carcinoma, and carcinoma in situ must be excluded. The basic laboratory testing includes a urinalysis and urine culture. If the patient reports a history of smoking and/or presents with unevaluated microhematuria, then urine cytology may be considered given the risk of bladder cancer. Urine culture may be indicated even in patients with a negative urinalysis in order to detect lower levels of bacteria that are clinically significant but not readily identifiable with a dipstick or on microscopic examination. The potassium sensitivity test has neither the specificity nor sensitivity to change clinical decision-making and is not recommended.
Baseline voiding symptoms and pain levels should be obtained in order to measure subsequent treatment effects. All patients should be asked to do a voiding diary (see Fig. 17-1 ) and fill out the O’Leary-Sant symptom and problem index ( Fig. 36.4 ). The validated pelvic pain urgency and frequency questionnaire may also be used.
A medical history should include associated diseases, such as migraines, fibromyalgia, sinusitis, drug hypersensitivity, sicca syndrome (dry eyes, dry mouth), Sjögren’s syndrome, vulvodynia, and irritable bowel syndrome.
Physical Examination
The abdominal and back examinations detect the presence of costovertebral tenderness and abdominal tenderness or mass. The external genitalia are examined for signs of infection and vulvar vestibulitis (tenderness over the vulvar vestibular or Bartholin’s glands). The pelvic examination includes a vaginal and urethral culture, if appropriate, evaluation for signs of atrophic vaginitis or a urethral caruncle, and a Papanicolaou smear if indicated. Careful palpation and perineometry may help evaluate the pelvic floor muscles to rule out pelvic floor dysfunction (the inability to optimally contract and relax the pelvic floor muscles). Evaluation of bladder and pelvic organ support is done in the dorsal lithotomy and standing positions to determine and grade bladder neck hypermobility, cystocele, enterocele, uterine prolapse, rectocele, and perineal descent. The posterior bladder wall and urethra should be palpated to check for tenderness and masses, and a bimanual examination should be performed to detect pelvic or adnexal masses and tender nodules. A rectovaginal examination is performed to evaluate tenderness along the uterosacral ligaments. Finally, a neurourologic examination ascertains the presence of the bulbocavernosus reflex and grades perineal sensation and anal sphincter strength.
Laboratory and Radiographic Evaluation
Initial laboratory examination should include urinalysis, urine culture and sensitivity, and measurement of postvoid residual urine volume (catheterized or with bladder ultrasound). Urine cytology is indicated in the presence of hematuria and persistent urgency. A 24-h voiding diary measures input and output, number and quantity of voids, and number and severity of leakage episodes. A renal ultrasound, intravenous pyelogram (IVP), or computed tomography (CT) scan is indicated in the presence of hematuria, history of recurrent UTI, or history of pelvic surgery. A voiding cystourethrogram is useful in ruling out vesicoureteral reflux and evaluating the bladder neck in patients with concomitant incontinence or suburethral diverticulum. Magnetic resonance imaging (MRI) may further delineate the urethra when evaluating for a urethral diverticulum. Awake cystoscopy is indicated in the presence of hematuria, persistent or recurrent UTI, or suspected fistula or urethral diverticulum.
Diagnostic Cystoscopy
Cystoscopy should be considered when the diagnosis is in doubt; it is not necessary for making the diagnosis in uncomplicated presentations. There are no agreed upon cystoscopic findings diagnostic for IC/BPS. The only consistent cystoscopic finding that leads to a diagnosis of IC/BPS is one or more inflammatory appearing lesions or ulcerations (as initially described by Hunner). The classic Hunner ulcer, an area of erythema with small vessels radiating to a central, pale scar after bladder filling, is found in only 8% of patients with IC.
Glomerulations (pinpoint petechial hemorrhages) may be detected on cystoscopy and can be consistent with IC/BPS but these lesions are commonly seen in other conditions that may coexist with or be misdiagnosed as IC/BPS, such as chronic undifferentiated pelvic pain or endometriosis. Glomerulations also may be present in asymptomatic patients undergoing cystoscopy for other conditions.
Urodynamic Tests
Urodynamic evaluations are performed on patients with hypersensitivity symptoms to evaluate the following features: volume at first sensation of bladder filling, first desire to void, strong desire to void, increased bladder sensation, maximum cystometric capacity, detrusor compliance, the presence or absence of detrusor overactivity, and reproduction of bladder pain and/or patients’ symptoms. Patients with IC often have symptoms suggestive of an overactive bladder. The ICS refers to the term “overactive bladder” as a storage phase disease diagnosed by clinical symptoms. Detrusor overactivity is a urodynamic observation characterized by involuntary detrusor contractions during the filling phase that may occur spontaneously or may be provoked. Patients with hypersensitivity disorders often demonstrate increased bladder sensation and bladder pain during filling cystometry. Increased bladder sensation is a urodynamic observation during filling cystometry and is defined as an early first sensation of bladder filling (or an early desire to void) and/or an early strong desire to void, which occurs at low bladder volume and persists.
defined sensory urgency as an abnormal first sensation on bladder filling <75 mL and a bladder capacity <400 mL in the absence of involuntary bladder contractions. Normal first sensation of filling occurs between 50 and 150 mL, with a first urge to void between 200 and 500 mL and a maximum capacity between 400 and 700 mL. found that patients enrolled in the NICDB had a correlation between reported daytime, nighttime, and 24-h frequency and both volume at first sensation to void (VFSV) and volume at maximum cystometric capacity (VMCC). VFSV decreased as awake frequency increased. Patients who voided equal to 5 times during awake hours had a mean VFSV of 114 ± 81 mL versus 74 ± 61 mL for those voiding >15 times. Similarly, this was seen with VMCC with mean volumes of 244 ± 149 mL versus 184 ± 114 mL, respectively, for those voiding equal to 5 times and those voiding >15 times. This same trend was seen with nocturia and 24-h voiding frequency. Patients with a 24-h voiding frequency of >15 times per day had a mean VFSV of 70 ± 59 mL and a VMCC of 190 ± 112 mL.
In addition to comparing a patient’s symptoms to urodynamic findings, a correlation has been made between urodynamic findings and cystoscopic findings, and a patient’s severity of disease. Most authors have noted a decrease in VFSV and VMCC. compared the findings of 150 women involved in the NICDB who underwent cystoscopy, bladder overdistention, and urodynamics. The mean VFSV was 81 ± 64 mL, and a mean VMCC was 198 ± 107 mL. Many authors feel that patients with a Hunner ulcer have a more severe form of IC. The NICDB noted that patients with a Hunner ulcer had a mean VFSV of 34.7 ± 20.5 mL. This was statistically lower than the VFSV of patients without a Hunner ulcer. None of the urodynamic criteria were statistically significant when related to the presence or absence of bloody effluent, presence and degree of glomerulations, presence of involuntary bladder contractions, or end-filling pressures. Twenty-six patients (17.5%) in this study had involuntary bladder contractions. Other studies have found that 5% to 26% of patients with the symptom complex of IC had involuntary bladder contractions. The original exclusion criteria for IC included involuntary bladder contractions; this is now a debatable issue. Currently, there are no agreed upon urodynamic diagnostic criteria for IC/BPS. Urodynamic evaluation may provide information regarding concomitant lower urinary tract symptoms. Patients with the symptom complex of a hypersensitive lower urinary tract tend to have an early first sensation of bladder filling, a decreased VFSV, and a decreased VMCC during urodynamic studies.
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