Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is one of the evil quadruplets – diseases coexisting with endometriosis. Etiology and even the way to obtain proper diagnosis is very debatable among providers. One of the mainstays of IC/BPS is pain with full bladder, and patients with this condition urinate often because they want to avoid pain and not because they have urgency. They also always wake up at night to urinate, so if patients do not have nocturia it almost always rules out the disease. Diagnosis of IC/BPS may be done based on the symptoms but some practitioners would use potassium sensitivity test or cystoscopy with bladder hydrodistension if necessary. Treatment consists of avoiding foods that irritate the bladder and increase the pain. Oral medications such as pentosan polysulfate sodium do not seem to be as effective. Patients with IC/BPS also very often have pelvic floor muscle spasm that may be primary to the onset of bladder pain, and treatment of this spasm may be the most effective way to treat IC/BPS. Pelvic floor physical therapy and botulinum toxin A injections to pelvic floor muscles (not bladder) may be very helpful. Cystoscopy with bladder hydrodistension seems to be more effective than other treatments for IC/BPS.
Editor’s Introduction
Interstitial cystitis/bladder pain syndrome (IC/BPS) is one of the evil quadruplets – diseases coexisting with endometriosis. Etiology and even the way to obtain proper diagnosis is very debatable among providers. One of the mainstays of IC/BPS is pain with full bladder, and patients with this condition urinate often because they want to avoid pain and not because they have urgency. Diagnosis of IC/BPS may be done based on the symptoms but some practitioners would use potassium sensitivity test or cystoscopy with bladder hydrodistension if necessary. Treatment consists of avoiding foods that irritate the bladder and increase the pain. Oral medications such as pentosan polysulfate sodium do not seem to be as effective. Patients with IC/BPS also very often have pelvic floor muscle spasm that may be primary to the onset of bladder pain, and treatment of this spasm may be the most effective way to treat IC/BPS. Pelvic floor physical therapy and botulinum toxin A injections to pelvic floor muscles (not bladder) may be very helpful.
What Is Bladder Pain Syndrome?
Definition
First described in the 1800s, bladder pain syndrome is a chronic disorder characterized by pelvic pain and voiding symptoms. This condition is known by several epithets and corresponding acronyms including interstitial cystitis (IC), painful bladder syndrome (PBS), bladder pain syndrome (BPS), and hypersensitive bladder syndrome (HBS). For simplification in this book chapter, we will refer to this syndrome as bladder pain syndrome or BPS. In 1987, the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases proposed diagnostic criteria for clinical trials; however, that definition is meant to be used in the research setting and does not translate well to clinical practice. In 2009, the Society for Urodynamics and Female Urology defined BPS with the following criteria:
An unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder
Associated with lower urinary tract symptoms of more than 6 weeks duration
In the absence of infection or other identifiable cause [1]
Ultimately, BPS is a clinical diagnosis based on symptoms that cannot be explained by more traditional problems such as bladder infection, bladder cancer, or other pelvic/bladder pathology. This definition does present BPS as a diagnosis of exclusion in part because the etiology of the disorder is still being explored.
Pathophysiology
Much progress has been made toward better understanding of the pathophysiology of BPS in the past two decades. While there are many theories as to the etiology of BPS, it is generally thought to be a pain disorder that likely has many potential triggers that initiate the symptoms. Even with the heterogeneity of this pain disorder there are certain characteristics that tend to be present in the majority of patients who have BPS. As in all patients with chronic pain there is generally a centralized pain component that results in allodynia, and urinary frequency is the hallmark of this central sensitization. Most patients also demonstrate evidence of urothelial dysfunction as well as peripheral sensitization with biopsy evidence of increased neural density and mast cell activation.
The urothelial dysfunction results in a deficiency of the glycosaminoglycan (GAG) layer of the bladder surface. Normal bladder epithelium is impermeable to irritants and urinary solutes, so the GAG layer deficiency in patients with BPS allows irritating solutes to penetrate into the bladder tissue, which is thought to result in localized inflammatory changes and localized upregulation (inflammatory cytokines, nerve growth factors, etc.). Several studies have suggested that there is an immune component in which upregulation of mast cell activation causes activation of capsaicin-sensitive nerve fibers that leads to inflammation which in turn damages the GAG layer of the bladder epithelium. This also leads to neurogenic upregulation [2].
Central sensitization plays a role in the development of BPS, as the prolonged exposure to noxious stimuli (i.e., bladder irritants) leads to activation of N-methyl-d-aspartate (NMDA) receptions in the dorsal horn of the spinal cord. NMDA receptor activation decreases the inhibition of dorsal horn neurons, which lowers the threshold for a stimulus to be perceived as painful. The process of central sensitization is key to many chronic pain disorders that are often associated with patients who have IC/BPS. Classic examples include fibromyalgia, vulvodynia, and endometriosis (see Chapter 2). These sensory processing abnormalities are self-perpetuating as nonpainful stimuli in sensitized patients are increasingly perceived as painful (e.g., 2 ounces of urine in the bladder feels like 20 ounces) leading to further C-fiber upregulation in the periphery as well as glial cell activation centrally. Some authors feel the persistence of neurogenic inflammation results in damage of bladder muscle fibers and bladder fibrosis [2, 3] that results in the contracted small capacity bladder that is seen in patients with long-standing untreated BPS.
There is no unified theory for the inciting event that leads to the development of BPS. There are many potential triggers with “insults” that can occur in the periphery or centrally that can result in the cascade of events that ultimately results in the symptoms of BPS. Theories include bacterial infections, autoimmune disorder, and environmental factors including stress and diet, as well as association with other pain disorders such as fibromyalgia, irritable bowel syndrome, and panic disorders. There appear to be significant genetic factors that contribute to the development of BPS as well as other chronic pain disorders [4]. Regardless of the original trigger, the end result is typically the same constellation of symptoms. One exception to this is ulcerative BPS, which is likely a unique entity requiring specific therapy [5].
Ulcerative Bladder Pain Syndrome
Also known as classic interstitial cystitis, Hunner-type IC, ulcerative IC, and BPS European Society for Study of Interstitial Cystitis (ESSIC) type 3C, ulcerative BPS has emerged as a discrete condition within the disease spectrum of BPS. This condition is defined by the presence of Hunner’s lesions on cystoscopy and occurs rarely in approximately 4% of cases [6]. This disease presentation tends to respond more reliably to specific therapies versus BPS in general [7]. There has been the proposal to treat BPS ESSIC type 3C as a discrete inflammatory disease process within the syndrome of BPS [5]. Patients with BPS ESSIC type 3C tend to have more severe pain and lower bladder capacity when they have a larger number of lesions. Despite increased symptom severity with increased lesions, this is not predictive of long-term response to interventions [8]. There are a number of interventions that benefit patients with Hunner’s lesions such as fulguration of lesions, steroid injection into lesions, and cyclosporine A [7]. (See the section “How Is Bladder Pain Syndrome Treated?)
How Common Is Bladder Pain Syndrome?
The prevalence of BPS differs widely depending on the manner in which epidemiological studies are conducted. Billing data, self-reported diagnosis, patient questionnaires, and medical record extractions have all been used in order to quantify the number of people affected by BPS. There is a significant difference in the prevalence of the syndrome in women versus men; the ratio of female to male individuals affected by BPS is five to one. For this reason, many studies have focused on the prevalence of BPS in women [7].
One of the most referenced studies on BPS prevalence is the RAND Interstitial Cystitis Epidemiology (RICE) Study. This population-based study showed that 2.70%–6.53% of adult women in the United States meet the criteria for BPS. Approximately 87% of women had sought medical care of their symptoms, and many had been evaluated by multiple providers, with a mean number of 3.5 physicians consulted among study participants. However, fewer than 50% had been given any diagnosis associated with their bladder symptoms and only 9.7% of the women who met the criteria for BPS based on the study definition had been assigned a diagnosis of BPS. This study highlights the fact that BPS is more prevalent than many clinicians recognize [9].
What Is the Typical Course and Impact of Bladder Pain Syndrome?
Based on available data, it is typical for BPS to be diagnosed in the fourth decade of life; however, there may be confounding factors of delayed diagnosis as detailed earlier. Many patients present with culture-positive urinary tract infections, but their symptoms fail to resolve with adequate treatment of infections. Patients may present with one symptom and then eventually develop all of the typical symptoms in BPS. It is common for patients to have “flares” of their symptoms that may last hours to weeks at a time [7].
The negative impact of BPS on quality of life is significant. Patients have high rates of poor sleep, depression, social functioning difficulties, and sexual dysfunction. The rate of moderate to severe sexual dysfunction is much higher in these patients and serves as a strong predictor of poor quality of life. The psychosocial impact of BPS is worse than in women with endometriosis, overactive bladder, and vulvodynia. Effective treatment of BPS is associated with improved sleep and sexual function and in turn associated with improved quality of life.
The economic impact of BPS is difficult to ascertain because of its unknown prevalence. The direct cost of doctor visits, hospitalizations, and therapies is greater than the mean annual per-person cost of disease such as diabetes and hypertension [10]. The more abstract costs such as lost economic contribution and productivity are also significant considering that most patients are diagnosed while they are working age and the condition is chronic. The cost to individuals should be considered as well. Patients with BPS typically have two to four times higher annual medical costs than age-matched controls [10]. Those individuals also suffer the economic burden of lost wages [7].
How Is Bladder Pain Syndrome Diagnosed?
History
Obtaining a detailed patient history is the first step in diagnosing bladder pain syndrome. Patients may initially present with only one complaint such as urinary frequency or dysuria and eventually develop additional features of BPS with urinary symptoms as well as pain. One defining feature of BPS is increased pain with increasing fluid volume in bladder. In addition to pain pattern, clinicians should evaluate for urinary frequency, urinary urgency, nocturia, and sexual dysfunction. Voiding patterns should be defined. A hallmark of BPS is frequent voiding for the purpose of pain relief. This must be differentiated from frequent voiding due to urge or avoidance of incontinence. Additionally, voiding volume is pertinent because patients with BPS have pain with bladder filling and void at lower bladder volumes (less than 120 mL) in order to relieve pain. Patients with PBS may describe “flares” of pain that may be associated with a number of stressors including diet, seasonal allergies, or sexual activity. Therefore, timing of symptoms can also be helpful in both initial diagnosis and choice of intervention [7].
Bladder diaries can be helpful in diagnosis of BPS and also serve as useful documentation when deciding whether or not an intervention for BPS is effective. Bladder diaries should include number of voids in a 24-hour period as well as details regarding urine volume, presence of pain, incidence of nocturia, presence of urgency, and episodes of incontinence. A bladder diary for one 24-hour period is adequate [11].
When reviewing past medical history, several conditions occur more frequently in patients with bladder pain syndrome than in the general population. Irritable bowel syndrome, fibromyalgia, vulvodynia, endometriosis, depression, anxiety, and systemic lupus erythematosus are all more common. Patients with BPS have a high rate of previous pelvic surgery although it is unclear whether this is a contributing factor or an intervention for an incorrect diagnosis in the past. A history of sexual abuse is more common in patients with pelvic pain compared to the general population. These conditions should be identified and treated as appropriate [7].
BPS has symptoms that overlap with those of other urologic conditions and pelvic pain syndromes, and a thorough history can distinguish it from those conditions. While patients with overactive bladder (OAB) will have symptoms of urinary frequency, patients will typically report that this symptom is associated with the fear of leakage of urine. Patients with BPS have frequency because of discomfort that is typically relieved by voiding. There is an overlap between these two disorders; it is thought that approximately 20% of patients with BPS will be found to have detrusor instability. Therefore, these mixed symptoms sometimes require therapy directed toward both etiologies. Patients with BPS will occasionally report leakage of urine yet the leakage that is reported is small in amount and often occurs without the patient experiencing severe urgency or undergoing stress maneuvers. This atypical loss of urine will often resolve with correction of the inflammatory changes within the bladder and treatment of the pelvic floor hypertonic dysfunction. BPS can present either as the patient’s chief complaint and source of pelvic pain or it can be a component of a complex pain disorder that might include other pain generators such as endometriosis (patients with endometriosis are four times more likely than controls to have BPS) or vulvodynia (50% of patients with BPS have vulvodynia). Patients with low voiding frequency and high-volume voids likely have another etiology for pain [2].
Supplemental Questionnaires
Like voiding diaries, questionnaires can be very helpful in both diagnosis and assessment for effectiveness in treatments. When initially diagnosing BPS, questionnaires improve efficiency and accuracy of diagnosis. The Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF)[12] and O’Leary-Sant Symptom Screener (OLS)[13] both elicit information about urinary symptoms essential to diagnosis of BPS. (See Appendix.)
Examination
Pelvic examination of a patient with symptoms suggestive of BPS involves a careful assessment of each pain generator and the determination of its involvement in the patient’s symptomatology. Patients with bladder pain syndrome typically will be found to have tenderness at the bladder base as well as hypertonic pelvic floor muscles that also are tender and reproduce the feeling of pressure or the need to urinate. The clinician can use this information to determine the potential source of the primary pain generator. Many patients have both a pelvic floor muscle contribution as well as bladder tenderness. Many patients will also report urethral burning yet with pain mapping the “urethral“ burning is often elicited by light touch above the urethral meatus – this is a classic finding of BPS. Pain mapping is an essential component of the physical exam. Patients should be evaluated for vaginitis, tenderness, and other potential source of pain or infection. Absence of bladder pain with palpation should decrease suspicion for BPS. Examination also identifies other factors that may be causing a patient’s symptoms such as fibroids, vulvar disease, urethral diverticuli, or pelvic organ prolapse. All of these conditions may potentially lead to high-frequency, low-volume voiding. A post-void residual should be determined at the time of exam to rule out urinary retention as a cause of symptoms [7].
Diagnostic Testing
Diagnostic evaluation beyond a thorough history and physical exam is not required, with the exception of urinalysis and urine culture. However, if there are any questions regarding the diagnosis, additional testing can be helpful.
Urinalysis/Urine Culture/Urine Cytology
Bladder pain and urgency are characteristic of acute cystitis and therefore urinalysis and culture are warranted in patients whose symptoms are suggestive of BPS. Patients with evidence of urinary tract infection (UTI) should be treated and reevaluated for symptoms when the infection has resolved because UTIs are relatively common among patients with BPS. Additionally, urinalysis showing microhematuria may prompt further evaluation with urine cytology, especially in patients at risk for bladder malignancies (e.g., tobacco users)[7]. When patients present with new bladder pain symptoms that started after a new sexual partner, evaluation of the vaginal canal for the presence of Mycoplasma or Ureaplasma should be considered. Some suggest all patients need to be tested, yet that is not universally accepted [14].
Cystoscopy
Although cystoscopic evaluation is a requirement for the restrictive definition of BPS intended for research, it is not necessary for clinical diagnosis. Performing cystoscopy has not been found to provide additional diagnostic information beyond that elucidated via history and physical exam. Multiple authors have demonstrated both false negatives and false positives when presence of glomerulations is used to rule in or rule out BPS. While cystoscopy alone can be misleading, it is essential in identifying those patients with ulcerative disease. Cystoscopy also allows the clinician to rule out other etiologies for the persistent bladder symptoms [6].
Urodynamics
Like for cystoscopy, the utility of urodynamics in BPS is ruling out other etiologies such as bladder outlet obstruction and detrusor overactivity. Therefore, if there is a question regarding the presence of these other conditions, urodynamic testing should be performed. Although patients with BPS have been found to have common findings such as early first sensation to void and decreased bladder capacity, these characteristics are not necessary for diagnosis [15]. Evaluation of urethral pressures during urodynamics will often demonstrate urethral pressures that are elevated (greater than 130 cm H2O) in patients who have pelvic floor hypertonicity. Voiding dysfunction due to the inability to completely relax the pelvic floor muscles is common in patients with hypertonicity and BPS [16].
Bladder Anesthetic Challenge Test
When the clinician suspects the bladder to be a source of pain, a relatively simple anesthetic challenge will often demonstrate for both the patient and the clinician that at least temporary relief of pain can be achieved. The placement of 20 mL of 2% lidocaine combined with 20,000 units of heparin can result in at least 2 hours of marked improvement in pain when pain is originating from the bladder. This diagnostic test has replaced the use of potassium chloride in many practices as a test of bladder hypersensitivity and pain [17].
How Is Bladder Pain Syndrome Treated?
The management of BPS should be guided by the following principles:
The initial treatment level should be tailored to the individual patient based on severity of symptoms, patient preference, and clinician judgment.
The clinician should target each pain generator and thus therapy will be individualized. Most patients will have both bladder and pelvic floor pain. Therapy should address both.
If in the best interest of the patient, multiple treatments may be started simultaneously.
Ineffective treatments should be stopped.
Pain management should be a central consideration throughout treatment, as the ultimate goal of intervention is to minimize pain and therapy side effects while maximizing patient function.
Treatment should be implemented from most to least conservative. Surgical intervention should be reserved for patients who are not responsive to conservative therapy with an exception for patients who are discovered to have Hunner’s lesions.
If there is no improvement of symptoms in a clinically meaningful timeframe, diagnosis should be reevaulated.
Recommendations for treatment of BPS are based on the American Urologic Association (AUA) guidelines for the diagnosis and treatment of BPS. The hierarchy of the treatment recommendations is based on potential benefit, risk–benefit profile, and severity and reversibility of adverse effects. Treatment is challenging because there is no one treatment that is reliably effective for the majority of patients. Therefore, a trial of multiple treatment approaches including multimodal therapy may be required before an effective regimen is identified for an individual patient.
First-Line Interventions
All patients should be offered these interventions when diagnosed with BPS [7].
Patient Education (Clinical Principle)
This element of treatment is important in setting patient expectations for their disease course and options for therapy. Patients should be counseled on normal bladder function and BPS including the fact that there is much still unknown about this condition. Patients should be educated about the various triggers to their symptoms and why treatment is typically multimodal. The concept of multiple pain generators and the need to treat each one is stressed so that the patient understands the reasoning behind each of the treatment modalities and gets her involved in her treatment decisions. Additionally, it is important for patients to understand that BPS is a chronic condition that may have periodic flares interspersed with asymptomatic periods.
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