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Interstitial cystitis/bladder pain syndrome
Introduction
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a heterogeneous and symptom-based condition marked by bladder or urethral pain and associated lower urinary tract symptoms, especially urinary frequency and urgency, in the absence of infection and other demonstrated pathology. Tremendous efforts have been made to gain an understanding of this disease, but the etiology remains unclear. This chapter will present current understanding and controversies surrounding nomenclature and definition of the disorder, pathogenesis, and diagnostic approach. Finally, management options, from conservative to surgical, are presented incorporating the latest clinical evidence and consensus guideline recommendations.
Nomenclature
Efforts to improve the clinical outcomes of women with IC/BPS have been complicated by a lack of international consensus on the definition of and diagnostic criteria for this challenging condition. In 1987, for research purposes, the National Institutes of Health (NIH) established standardized diagnostic criteria for IC ( ; Box 35.1 ). However, these expert consensus–based research criteria were quite restrictive and were found to be less useful for clinical purposes. In fact, among 269 women followed for 1 year as part of the National Interstitial Cystitis Database study, 60% of those thought very likely to have IC would not be diagnosed based on these criteria ( ).
Box 35.1
(From Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis , Bethesda, MD, August 28–29, 1987, National Institutes of Health. J Urol . 1988;140:203.)
The 1987 National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Diagnostic Criteria for Interstitial Cystitis
Category A: At least one of the following findings on cystoscopy:
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Diffuse glomerulations (≥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 a
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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 a
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Symptoms relieved by antimicrobial agents (antibiotics, urinary antiseptics), anticholinergics, or antispasmodics a
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Urinary tract infection in the past 3 months a
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Active genital herpes
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Vaginitis a
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Uterine, cervical, vaginal, or urethral cancer within the past 5 years a
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Bladder or ureteral calculi a
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Urethral diverticulum a
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History of cyclophosphamide or chemical cystitis or tuberculosis or radiation cystitis
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Benign or malignant bladder tumors
Relative exclusion criteria.
Over the last 20 years, various professional organizations have proposed different nomenclature for painful bladder conditions, with differing diagnostic recommendations. In 2002, the International Continence Society focused on bladder pain and introduced the term painful bladder syndrome (PBS). PBS was 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 ( ).
In 2008, the European Society for the Study of Interstitial Cystitis (ESSIC) reached a consensus to rename IC and PBS to 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. In a departure from other contemporaneous guidelines, ESSIC recommended that classification of BPS types might be performed according to findings at cystoscopy with hydrodistention, as well as histologic findings in bladder biopsies ( Box 35.2 ). Confusable diseases as the cause of the symptoms must be excluded ( Table 35.1 ). The presence of other organ symptoms, as well as cognitive, behavioral, emotional, and sexual symptoms, should be addressed.
Box 35.2
(From van de Merwe JP, Nordling J, Bouchelouche P, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol . 2008;53:60. With permission.)
Schematic Representation of the ESSIC Approach for Diagnosis of Interstitial Cystitis/Bladder Pain Syndrome (2008)
TABLE 35.1
Confusable Diseases for Bladder Pain Syndrome in Women
(Modified from van de Merwe JP, Nordling J, Bouchelouche P, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol . 2008;53:60.)
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The diagnosis of a confusable disease does not necessarily exclude a diagnosis of bladder pain syndrome.
CT , Computed tomography; IVP , intravenous pyelogram; MRI , magnetic resonance imaging.
The terminology most widely used clinically in the United States is IC/BPS, defined by the Society for Urodynamics and Female Urology as “[a]n 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 allows treatment to begin after a relatively short symptomatic period (6 weeks rather than 6 months, as in the ESSIC definition) and was used by the American Urological Association (AUA) in their IC/BPS guidelines published in 2011 and amended in 2015 ( ).
Recently, international IC/BPS experts have called for the development of more consistent nomenclature and guidelines for IC/BPS ( ; ). It has long been recognized that some patients with IC/BPS have erosive bladder lesions (“Hunner lesions”), and increasing evidence supports different treatment outcomes in patients with such lesions. Given this, interest has grown in classifying and defining IC/BPS based on the presence or absence of these lesions, sometimes called Hunner lesion disease versus non–Hunner lesion disease, or ulcerative IC and nonulcerative IC (Whitmore et al.). We anticipate that future diagnostic classifications for IC/BPS are likely to include this categorization.
Epidemiology
First described over a century ago by , , and , IC/BPS was not studied from an epidemiologic standpoint until the last several decades. Likely related to changing definitions of IC, reported prevalence rates varied substantially among early population-based studies, ranging widely from 18 to 865 women per 100,000 (0.02%–0.9% prevalence; ). Use of more modern definitions and varying study methodology led to subsequent prevalence estimates ranging from 0.45% ( ) to as high as 12.6% ( ).
Given the lack of objective tests available to diagnose the condition, epidemiologic studies generally fall into three categories: self-report studies, symptom assessments, and review of billing data/diagnosis codes ( ). These varied methods likely contribute to the wide range of estimates regarding burden of disease. In a population-based, cross-sectional survey of individuals in the Boston area, reported the prevalence of PBS as 0.83% to 2.71% of women, depending on the definition used. Perhaps the most rigorous large-scale estimate of disease prevalence is provided by the RAND Interstitial Cystitis Epidemiology (RICE) study, a US population-based telephone survey. RICE investigators estimated the prevalence of IC/BPS in women 18 years of age and older to range from 2.7% to 6.5%, which translated to 3.3 to 7.9 million adult US women ( ). Prevalence estimates in female populations are consistently higher than in male populations, with investigations based on diagnosis in clinical practice suggesting a female-to-male ratio of 5:1 ( ), whereas population-based studies find a lower ratio (2–3:1; ). In population-based studies, IC/BPS is not consistently associated with any racial/ethnic background but is most common in middle-aged groups (40–59 years range) and those with lower socioeconomic status ( ; ).
Regardless of the exact prevalence of IC/BPS, this condition has been shown to overlap with many other pain syndromes and has a significant impact on patients’ quality of life. Many IC/BPS patients suffer from fibromyalgia, irritable bowel syndrome, anxiety, and depression ( ; ; ). As many as 85% of patients with IC/BPS will be diagnosed with high-tone pelvic floor dysfunction or levator ani pain, which often manifests as general pelvic pain, dyspareunia, urinary hesitancy, and difficulty with defecation ( ). Epidemiologic studies confirm that women with IC/BPS symptoms have poorer self-reported physical and mental health than the general US population ( ).
Etiology
The etiology of IC/BPS is currently unknown and likely to be multifactorial. A comprehensive review of this broad topic is beyond the scope of this chapter; therefore, we briefly review several potential IC/BPS etiologies, including both peripheral and central causes, with a focus on recent research results.
Epithelial alterations
Increasing evidence suggests that alterations of the urothelium (specialized transitional epithelium lining the renal pelvis, ureters, and bladder) play an important role in IC/BPS. Both molecular and structural uroepithelial changes have been observed in patients with IC/BPS and in animal models of the disease ( ). The urothelium forms an efficient barrier against potentially harmful urine components. Also, activation of urothelial cells by chemical, thermal, or mechanical stimuli can cause the release of various mediators or neurotransmitters, which may influence nerve activity, detrusor cell contraction, and ultimately bladder function ( ). Thus, a wide variety of epithelial dysfunctions, such as altered expression or sensitivity of molecular targets, channels, or receptors, might lead to abnormal sensation and function such as that seen in IC/BPS.
Histologic examination of the bladder in IC/BPS differs based on the presence or absence of Hunner lesions identified during cystoscopy (see Diagnostic Cystoscopy ). The bladder mucosa of patients with Hunner lesion disease is characterized by chronic inflammatory changes, including lymphocytes, plasma cells, macrophages, neutrophils, and mast cells, particularly between the urothelium and lamina propria (suburothelium) ( ). Similar inflammation is not seen in non–Hunner lesion IC/BPS. Others have reported that findings of pancystitis, clonal B-cell expansion, and epithelial denudation are unique to Hunner lesion disease ( ). These differences suggest that different disease mechanisms are involved in IC/BPS patients with and without Hunner lesions, supporting proponents of new IC/BPS diagnostic classifications that separate Hunner lesion disease from other types of IC/BPS ( ).
Other mucosal abnormalities do not clearly differ in IC/BPS patients with or without Hunner lesions. Immunohistological studies of bladder mucosa from bladder biopsies of IC/BPS patients with and without Hunner lesions have demonstrated differences in markers related to inflammation, angiogenesis, fibrosis, and denudation compared with controls. In some cases, the changes correlate with symptom outcomes. reported increased TNF-α, VEGF, CD31, and TGF-β in IC/BPS patients with and without Hunner lesions compared with controls, whereas increased mast cell tryptase and collagen were observed in Hunner lesion patients only (compared with non–Hunner lesion patients and controls). The increased expression of CD31, a protein marker related to angiogenesis, in IC/BPS patients had the highest correlations with pain and urinary symptoms.
Gene expression studies in RNA taken from bladder biopsies also suggest that disease mechanisms may differ in IC/BPS patients with and without Hunner lesions. In one study, patients with Hunner lesions had a distinct gene expression profile, with upregulation of genes involved in biological pathways related to cell proliferation, the immune system, and infectious processes ( ). The RNA sequence analysis from IC/BPS patients without Hunner lesions did not differ from controls.
An elevated mast cell count in the bladder muscularis was long promoted as a diagnostic histopathologic feature of IC/BPS, and different values for mast cell counts in the detrusor layer were proposed as a diagnostic marker. studied 69 patients with IC/PBS (diagnosed based on the 1987 NIH criteria and including both ESSIC types 2 and 3) and 37 controls (with and without non-IC/BPS chronic cystitis) and demonstrated that the presence of mast cells correlated with the level of background lymphoplasmacytic infiltrate, but not with the diagnosis of IC. This suggests that mast cell counts are not of value in diagnosing IC/BPS.
The urothelium’s surface coat of glycosaminoglycans (GAG) has been proposed to be deficient in some patients with IC/BPS. When the GAG layer is damaged, the urothelium has increased permeability to urine components, which may result in local inflammation, neural sensitization, and subsequent pain, frequency, and urgency. Important components of the GAG layer include chondroitin sulfate, hyaluronic acid, heparin sulfate, dermatan sulfate, and keratin sulfate ( ), and early research identified a lack of chondroitin sulfate in the GAG layer of IC/BPS patients ( ). Several agents with GAG-like properties, such as sodium hyaluronate, heparin, and pentosan polysulfate, are administered intravesically as treatment for IC/BPS, based on the hypothesis that replenishing the GAG layer might lead to urothelial layer recovery. Indeed, intravesical instillation of chondroitin sulphate into the rat bladder was shown to restore a damaged epithelial permeability barrier ( ).
Alternatively, dysfunction in other components of the urothelium may also be related to increased permeability. considered electron microscopy characteristics of the urothelium and demonstrated defects in umbrella cells (denudation, increased pleomorphism, and decreased microplicae of the cell membrane) in patients with IC/BPS (diagnosed using ESSIC 2008 criteria) compared with controls. Importantly, the severity of these defects correlated with symptom severity and bladder capacity.
Neurogenic inflammation
Neurogenic inflammation involves the enhanced release of proinflammatory neuropeptides (such as substance P) from sensory and/or sympathetic nerves, which can lead to persistent afferent nerve sensitization and local inflammatory changes. This process is mediated by mast cells, as the neurotransmitters released by peripheral neurons induce mast cell degranulation and the release of additional proinflammatory mediators. It is proposed that the inflammatory mediators’ actions on afferent neurons create a positive feedback loop, resulting in altered neural plasticity and central nervous sensitization in the dorsal root ganglia and the upper spinal cord and contributing to symptom persistence in IC/BPS ( ). This process, mediated by mast cells, has been proposed to be a nidus for induction, establishment, and chronicity of the various tissue changes seen in IC/BPS. Other conditions in which neurogenic inflammation may be implicated include irritable bowel syndrome, vulvodynia, migraines, and fibromyalgia, conditions that frequently overlap with IC/BPS.
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/BPS report a history of urinary tract infection 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/BPS.
More recently, molecular methods such as 16S rRNA rapid next-generation gene sequencing and expanded quantitative urine culture techniques have been employed to demonstrate that the lower urinary tract is not sterile, and alterations in the bladder microbiome (“dysbiosis”) have been identified that are associated with other chronic urinary tract conditions, such as urgency urinary incontinence ( ). In the largest study to date focused on the bladder microbiome in women with IC/BPS, compared microbiota in voided urine specimens obtained from 181 female IC/BPS and 182 female control participants. IC/BPS participants had a clinical diagnosis of IC/BPS, as well as current bladder pain or discomfort and associated urologic symptoms. A total of 92 bacterial species (41 genera) were identified, with similar mean species counts in IC/BPS and control participants (2.49 ± 1.48 vs. 2.30 ± 1.28). The species composition did not significantly differ between IC/BPS and control participants. Testing of individual genera showed a lower prevalence ( P = .002) and relative abundance ( P = .001) of Corynebacterium among IC/BPS participants compared with controls. Overall, this and smaller studies have reported differing and inconclusive results related to dysbiosis and IC/BPS, and more research is needed ( ; ).
Centralized pain processing
Women with IC/BPS frequently have other concurrent functional pain syndromes, including fibromyalgia, irritable bowel syndrome, and vulvodynia. A key component of these conditions is diffuse hyperalgesia (increased pain to normally painful stimuli) and/or allodynia (pain to normally nonpainful stimuli), suggesting a fundamental problem with pain and/or sensory processing in the central nervous system (CNS), rather than a peripheral abnormality originating from the location of experienced pain ( ). Some studies suggest that patients with non–Hunner lesion IC/BPS are more likely to have such concurrent disorders, although results are conflicting ( ; ). This potential difference has led experts to suggest that IC/BPS without Hunner lesions might share a neurophysiologic dysfunction affecting the CNS with the other functional pain syndromes. Regardless of the presence or absence of Hunner lesions, IC/BPS patients who have other concurrent pain syndromes are likely to have dysfunction in central pain pathways and increased pain perception. The mechanism(s) underlying central pain amplification and sensitization remains unclear. Increasing evidence suggests this may include altered processing of afferent signals in the brain (see below). Central visceral hypersensitivity/pain may also involve the persistent activation of dorsal horn neurons, resulting in changes within the spinal cord that can mediate pain long after resolution of inflammation or other pelvic insult.
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