Clinical guidelines for interstitial cystitis and hypersensitive bladder syndrome

Authors


Yukio Homma md phd, Department of Urology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyoku, Tokyo, 113-8655, Japan. Email: homma-uro@umin.ac.jp

Abstract

A clinical guideline and algorism for interstitial cystitis and hypersensitive bladder syndrome has been developed by a group of East Asian urologists as a revised form of the Japanese guideline for interstitial cystitis. The guideline defines interstitial cystitis (IC) as a disease of the urinary bladder diagnosed by 3 requirements; 1) a characteristic complex of lower urinary tract symptoms, 2) bladder pathology such as Hunner's ulcer and bladder bleeding after overdistension, and 3) exclusions of confusable diseases. The characteristic symptom complex is termed as hypersensitive bladder syndrome (HBS), which is defined as bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain. For the definite diagnosis of IC, cytoscopy or hydrodistension is crutial; HBS is the diagnosis when IC is suspected but not confirmed by the 3 requirements. Numerous therapeutic options are available; however, most of them lack in high level of evidence, leaving a few as recommended therapies. Etiology of IC are multifactorial; the interaction among nervous, immune and endocrine factors forms a vicious cycle, provocating and maintaining inflammatory reactions in the bladder. The inclusion and efficacy criteria for clinical trials should be standardized to enhance the clinical research for this disabling disease, which has proved to be more prevalent than previously believed.

Introduction

Interstitial cystitis (IC) is a disease of the urinary bladder with lower urinary tract symptoms such as bladder hypersensitivity, urinary frequency, and bladder pain and resulting in serious impairment of quality of life. In Asia the research and medical care of IC has been sparse because of an assumption that IC is very rare. In recent years, the realization that IC is a common disease in Asia has lead to an increase in academic and social activities regarding IC. However, the etiology of IC has not yet been clarified, which introduces confusion to the disease definition, and complicates its diagnosis and treatment. Thus the present article is an attempt to develop a clinical guideline, which is targeted at healthcare professionals including specialists in urology and women's health care who may engage in the diagnosis and treatment of IC and IC-related conditions.

Methods

The Japanese IC guideline, which was written by SICJ members in 2006 and endorsed by the Japanese Urological Association1,2 was used as the basis. For the Japanese guideline 1350 articles searched by the PubMed database in 2005 with the keyword, ‘interstitial cystitis’, were surveyed. For the present guideline, the articles published from 2006 to 2008 were additionally surveyed. Other sources of references included the reports of the International Consultation of Interstitial Cystitis in Japan (ICICJ),3,4 International Consultation on Incontinence (ICI) report,5 and the Guideline for Chronic Pelvic Pain by the European Association of Urology.6 The members met three times for discussion.

Definition

We define interstitial cystitis as a disease of the urinary bladder diagnosed by three conditions; lower urinary tract symptoms, bladder pathology and exclusions of confusable diseases. The characteristic symptom complex is termed as hypersensitive bladder syndrome (HBS), which is defined as bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain.

Despite its long history7 there is no widely accepted definition of IC.8,9 The National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) consensus criteria, which were developed to ensure the comparability of patients enrolled in clinical studies,10 would be too restrictive for clinical diagnosis.11

Due to its unclear definition, many terms that refer to IC or IC-related conditions have been used:12 interstitial cystitis (IC), painful bladder syndrome (PBS), chronic pelvic pain syndrome (CPPS), IC/PBS (PBS/IC), IC/CPPS (CPPS/IC) and bladder pain syndrome (BPS) are examples. IC has been used since the nineteenth century and is most universally recognized as a disease entity in academic, medico-legal or medico-economical societies. Meanwhile IC intuitively indicates inflammation in the interstitum, which is not necessarily true histopathologically.13 PBS has been used in various meanings since the 1980s,14 and was defined in 2002 as the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as frequency and nocturia in the absence of proven pathologies.15 PBS is recognized as an umbrella term with IC as a sub-type, which implicates that PBS includes IC.16 CPPS refers to a symptom syndrome with chronic pelvic pain15 resulting from a variety of diseases including IC.17 BPS is also a pain syndrome proposed by the European Society for the Study of IC/PBS (ESSIC) to replace the term IC.18 Chronic pain syndromes would be appropriate for IC or IC-related conditions,8 because bladder and/or pelvic pains are characteristic to those conditions,16 and they show substantial clinical overlap with other pain syndromes like fibromyalgia.19 Unfortunately these terms would be inappropriate somehow; IC or IC-related conditions show high diversity in symptoms, and a significant proportion of IC patients do not complain of pain but relate their feelings to pressure and discomfort.20 According to the definition by the International Association for the Study of Pain,21 pain is ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’, thus includes pressure or discomfort as a kind of pain. However, it would be unrealistic for common physicians and patients to use ‘pain’ to describe pressure or discomfort in accord with the scientific definition. Patients not complaining of pain would remain undiagnosed for IC, if only pain syndromes are applicable to IC or IC-related conditions.14,22 The term ‘IC/PBS’ inclusively covers diverse patient populations from those meeting NIDDK criteria to those only having bladder pain. However, this double-barreled term is a chimera combining a disease name and a symptom syndrome name, and is thus linguistically inappropriate and misleading.

In the present guideline, we have defined IC as ‘a disease of the urinary bladder diagnosed by three conditions: (i) lower urinary tract symptoms such as bladder hypersensitivity, urinary frequency, bladder discomfort and bladder pain; (ii) bladder pathology such as Hunner's ulcer and mucosal bleeding after over-distension; and (iii) exclusions of confusable diseases such as infection, malignancy and calculi of the urinary tract.2 For the symptoms, we propose a new symptom syndrome, ‘hypersensitive bladder syndrome (HBS)’.23 HBS could be defined as bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain if it should appear like the definition of overactive bladder syndrome (urinary urgency, usually associated with urinary frequency, with or without urgency incontinence). Increased bladder sensation is defined as the early and persistent desire to void.15 Hypersensitive bladder was once used as a term for idiopathic sensory urgency and ‘early’ IC,24 and recently it has been implicated with overexpression of TRPV1 mRNA,25 responsiveness to intravesical Resiniferatoxin26 or possible overlapping with overactive bladder syndrome.27 Thus HBS would be a clinical entity that is more inclusive than pain syndromes: it incorporates patients complaining and not complaining of pain.23 HBS can be used as a descriptive term for symptom complex, or as a diagnostic name for the condition that is suspected of IC but has not fulfilled all of the requirements for IC diagnosis. For the bladder pathology, bladder bleeding after overdistension may not be highly sensitive28 or specific,29,30 although it would be the sole abnormal endoscopic finding when Hunner's ulcer is absent.

Etiology and pathogenesis

Etiology of interstitial cystitis would be multifactorial. The interaction among nervous, immune and endocrine factors forms a vicious cycle, provoking and maintaining inflammatory reactions in the bladder.

Defective or dysfunctional bladder epithelium

The glycosaminoglycan (GAG) layer protects the bladder mucosa as a chemical barrier against urine. If it is defective, infiltrated urine would induce submucosal inflammation, stimulating sensory nerve fibers and causing frequency and pain.31 However, the reason why the GAG layer becomes defective has been unknown. Anti-proliferative factors (APF), detected in the urine of IC patients, downregulate gene expressions that stimulate proliferation of bladder epithelial cells and upregulate genes that inhibit proliferation, leading to urothelial under-maturation and dysfunctions.32,33 The factor increased the paracellular permeability,34 and can be potentially a specific diagnostic biomarker for IC. Aberrant epithelial expression of functional proteins such as E-cadherin, chondroitin sulfate, perlecan, biglycan, decorin, ZO-1, uroplakin, keratin and syndecan-1 can partially explain dysfunctional bladder epithelium.35–38 Upregulation of TRPV1,25 increased the release of adenosine 5′-triphosphate (ATP)39 or decreased production of PGE2 from the urothelium40 may play a role in pathogenesis of hypersensitivity or inflammation. However, few differences in gene expression were found in cultured keratinocyte of IC patients.41

Mast cell activation and/or inflammation

Mast cells are a central player in the inflammatory process: they release potent inflammatory mediators such as histamine, leukotriene and serotonin, and also interact with immunoglobulin E (IgE) antibodies, other inflammatory cells and nervous systems.42,43 The mast cell count is increased in the bladder tissue from IC, but the increase is not specific to IC and unclear in non-ulcer type IC.42,44,45 Inflammatory mediators including nitric oxide are concentrated in the affected bladder tissue,46,47 and interact with each other to enhance the activities; that is, leukotriene D4 potentiates histamine-induced increase in the intracellular calcium concentration.48 Blockade of interferon-gamma-inducible protein-10 (CXCL10), a potent inflammatory chemokine, inhibited cyclophosphamide-induced cystitis in mice.49

Infection

Infection of microorganism has never been identified as the direct cause of IC.50 No study has proven overproduction of urinary IgA and IgG,51 presence of bacterial 16SrRNA genes by PCR,52 or viral genes.53 It is widely recognized that antibiotic treatment is ineffective for IC. As the symptoms flare, mechanisms other than infection should be considered as the trigger.54 Yet, infection is occasionally an associated factor to initiate or worsen IC.55

Urinary toxic agents

Toxic agents in the urine, for example, potassium ion, may distort epithelial function of the urinary bladder and cause symptoms. Urine is necessary to provoke bladder inflammation induced by protamine injection.56 One hypothesis is that heat labile cationic urine components of low molecular weight exert toxic effects to bladder mucosa.57 IC-like symptoms by chronic ketamine abuse may be related to the toxic effects of ketamine and its metabolites.58 Urinary pH alone is unlikely to pronounce pain symptoms.59

Hypoxia

A decrease in the microvascular density in the submucosal layer is found in IC.60 Bladder vascular perfusion is reduced by bladder filling in IC, while it is rather increased in controls.61 Hyperbaric therapy is known to relieve IC symptoms. It is conceivable that the impaired blood circulation in the bladder is related to IC. In the affected bladder apoptotic activity of microvascular endothelial cells was increased.62

Impaired pelvic health

Women with IC have often the history of hysterectomy, cesarean births, miscarriage, stillbirth or abortion.63,64 Pelvic surgeries can be the trigger of the symptom development. The symptoms are likely to be affected by menstruation cycle.63 Both IC symptoms and irritable bowel syndrome were improved by treating small-intestinal bacterial overgrowth, which allegedly potentiates visceral hypersensitivity.65

Immunity and allergy

A number of reports suggest the existence of auto-antibodies in IC patients.66–69 The primary antibody detected in IC is anti-nuclear antibody, which is similar in auto-antibody profile to systemic autoimmune diseases such as Sjogren's syndrome.70 Mice immunized by bladder homogenate develop autoimmune cystitis comparable to IC.71 Increase of specific IgE is implicated with pathogenesis in a subset of IC patients.72 Reduced estrogen receptor β signaling may have a role in the pathogenesis through hyperactivation of T cells and autoimmune destruction of urothelium.73 However, the specific auto-antibody has not been identified in IC.

Neurogenic inflammation

Abnormality in the nervous system is an important potential etiology of IC. Nervous system is affected in IC patients;74–76 for example, predominance of the sympathetic nervous system,77 increased tyrosine hydroxylase, activation of purinergic nerves, and decreased expression of the S-100 family in Schwann cells.78–81 Ultrastructural histopathology showed characteristic features of neurogenic inflammation in IC.82 Inculcation of pseudorabies virus in the abductor caudalis dorsalis resulted in cystitis with mast cells accumulated in the mouse bladder wall.83

Emotion and autonomic nervous system

Interstitial cystitis is associated with increased sympathetic tone along with decreased cortisol level.84,85 Multiple diagnoses with other ill-defined diseases including irritable bowel syndrome, pelvic floor tension myalgia, abdominal wall myalgia, and vulvodynia are common,84,86 and a history of abuse or depressed psychological profiles were identified.87–92 Patients with a sexual abuse history are likely to present more pain and fewer voiding problems.93 Stress reduction is therapeutically beneficial for the symptom relief.94 These facts suggest interaction between the development of IC symptoms and central sensitization to mental stress.

Interaction among pathogenic factors

No single factor of the above mentioned etiologies alone could explain the entire process of IC pathogenesis; the etiology of IC is a complex interaction among nervous, immune, and endocrine systems.95 For example, mast cell activation by adjacent nerve endings can be affected by estradiol and corticotrophin-releasing hormone (CRH).96 Urinary levels of tryptase, nerve growth factor, neurotrophin-3 and glial cell line-derived neurotrophic factor increased in IC.97 The co-expression of stem cell factor and interleukin-6 (IL-6) is implicated with epithelial migration of mast cells.42 A nuclear factor-kappa β subunit was overproduced and the expression of IL-6 gene increased five times after activation of NF-kappa β in IC.98 Neural upregulation, both peripheral and central, is presumed to maintain the chronicity of symptoms,99,100 and cross talk in pelvic organs suggests a mechanism by which bowel or uterine pathology modulates the IC symptoms.101 A hypothetical pathway would be that the events such as injured urothelium and/or reduced oxygen tension initiate inflammatory reactions including overproduction and/or under-degradation of cytokines and growth factors, infiltration of immunocompetent cells such as mast cells and upregulation of sensory nerves, forming a vicious cycle to enhance inflammation in the bladder interstitum. In this regard, IC is a neuro-immuno-endocrine disorder or an ‘over healing’ disorder of the urinary bladder.46

Epidemiology

Recent studies uniformly indicate a higher prevalence of interstitial cystitis (including suspected) than previously believed, roughly one percent.

In Finland, the prevalence was estimated at 10.1 cases per 100 000 (0.01%) in 1975 based on positive symptoms, negative urinary tract infection and positive bladder biopsy.102 Following studies in 2002 indicated it as 450 per 100 000 (0.45%), and more recently it was 680 per 100 000 (0.68%) for a probable IC and 300 per 100 000 (0.3%) for a definite diagnosis of IC.103,104 The prevalence of 306 per 100 000 (0.3%) was reported in 2007 in Austria.105 In the United States, a questionnaire survey in 1987 indicated at least 43 500 IC patients and 217 500 possibly IC patients (0.014% and 0.07%, respectively). A report in 1994 suggested a prevalence of 0.5% of the total population.106 A survey with female nurses in 1999 estimated 52 to 67 per 100 000 (0.05 to 0.06%).107 A study using the managed care database showed 197 female and 41 male patients with IC per 100 000 (0.19% and 0.04%), respectively.108 The recent study indicates prevalences of IC symptoms of 1.3% in men and 2.3% in women.64 No evident racial/ethnic disparity or limited gender disparity exists in the prevalence of symptoms.89,109

In Japan, the prevalence was reported in 1998 to be only 2 per 100 000 patients by a questionnaire survey of 300 major hospitals.110 Japanese patients tended to be older (52.9 years in average) than those in Europe and the United States.111 This may indicate that Japanese patients have had symptoms for a long time before diagnosis. However, a recent epidemiological investigation in Japan found that 1.0% of the general population experienced bladder pain every day.112 In Korea, the results of the PUF questionnaire indicated a much higher prevalence (6.2%) of possible IC in women. In Taiwan, a study inquiring 1271 female adults aged 30 years and older by the O'Leary-Sant symptom/problem score disclosed that 0.31% of the surveyed women had a probable IC.

Known risk factors include smoking, depression, generalized pain disorders, irritable bowel syndrome, hysterectomy, and urinary tract infection.64,87,113 The economic burden is estimated to be substantial in the United States.114,115 Because of misdiagnosis, the true burden of IC on the health care system in the United States is probably underestimated.

Quality of life

Interstitial cystitis is a disease which profoundly affects patients' quality of life due to disabling symptoms.

A study evaluated quality of life (QOL) in 424 patients by Short Form 36 (SF-36),116 reporting that about 80% of the patients felt adverse affects of IC on daily living and social lives. Two subsequent studies confirmed that IC patients had significantly worse QOL by SF36 scores in many aspects compared with age-matched women without IC.117,118 A Japanese study found severely impaired QOL in IC patients by SF-36 and the King's Health Questionnaire (KHQ) scales.119 It is even worse when compared with the patients with chronic renal failure requiring hemodialysis, Crohn's disease, systemic lupus erythematosus or rheumatoid arthritis. Most patients feature significant depression and anxiety.90 Impairment in mental health dimension was demonstrated by specific scales for depression.118 Sexual functioning, employment and pain issues predict mental and physical domains in women with long-standing symptoms.120–123

Diagnosis

Interstitial cystitis is diagnosed by three requirements: symptoms (hypersensitivity, urinary frequency, bladder discomfort, and bladder pain), cystoscopic findings (Hunner's ulcer or bladder bleeding after hydrodistension) and exclusion of confusable diseases. Cytoscopy or hydrodistension is crucial for definite diagnosis. Hypersensitive bladder syndrome (bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain) can be the diagnosis when interstitial cystitis is suspected but not confirmed by the requirements. Unexplainable urinary frequency is highly suggestive of interstitial cystitis.

There are no established diagnostic criteria for IC.8,9 Two approaches have been undertaken; one is to depend on highly specific criteria such as NIDDK research criteria124 and the other is to adapt symptom-based criteria to increase the sensitivity of diagnosis by advocating the terms such as painful bladder syndrome (PBS) or chronic pelvic pain syndrome (CPPS). In the present guideline, we define IC by three requirements: symptoms such as hypersensitivity, urinary frequency, bladder discomfort and bladder pain, cystoscopic findings proving pathologies in the urinary bladder and exclusion of other diseases explainable for the symptoms and findings.2 Also we define hypersensitive bladder syndrome (HBS) as a symptom complex of bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain.23 HBS may be used as a tentative diagnosis for the condition that is suspected of IC but has not fulfilled the three requirements for IC diagnosis. Of primary importance in practice is to suspect IC when a patient complains of unexplainable urinary frequency.125–127

Symptoms

Common symptoms of IC include urinary frequency, nocturia, urinary urgency, bladder hypersensitivity, bladder discomfort, and bladder pain.116 These symptoms are collectively called hypersensitive bladder syndrome (HSB) in this guideline. Symptoms are susceptible to dietary, environmental and mental stress with variable remissions and exacerbations.128 The onset of symptoms may be either gradual or rapid.129 O'Leary- Sant's Symptom and Problem Indices are most commonly used for the symptom assessment,130 although the ‘urgency’ is not related to incontinence in many patients.131,132 Other symptom scales including Wisconsin Symptom Instrument133 were equally responsive and could be used as the assessment tool.134 Symptom scores alone have sufficient specificity to serve as the diagnostic indicator,135 and the typical symptoms are highly diagnostic of IC.136 The most typical symptom of IC would be bladder pain, especially pain worsened during holding urine and relieved after voiding. Pain may be felt in the perineum, in the pelvis, or during sexual intercourse.137,138 However, it should be noted that a substantial portion of patients do not complain of pain.22,111,139,140

Clinical examinations

Tenderness in the bladder may be noted by pelvic examination. Pain or tenderness at a specific area of the pelvic floor, in particular unilaterally, may indicate pelvic floor muscle disorder. Urinalysis usually shows no abnormality,141 although microscopic hematuria is noted in a substantial portion of cases.142 Voiding recording is indispensable to confirm decreases in voided volume or functional bladder capacity (e.g. less than 200 mL).11 In urodynamic studies detrusor overactivity may be present. Reduced bladder capacity without detrusor overactivity (bladder hypersensitivity) is suggestive of IC.24,143,144 Pain but not detrusor overactivity elicited by ice-water test is highly predictive of bladder hypersensitivity.145

Cystoscopy

Cystoscopy is needed to identify Hunner's ulcer,146 the positive specific findings of IC. It can also identify other pathologies in the bladder (e.g. bladder stone or cancer).116 In patients with untreated IC, a strong correlation between pain and cystoscopic findings was observed.147 Typically an ulcer is recognized as a well-demarcated reddish mucosal lesion lacking in the normal capillary structure. It is occasionally associated with covering fibrin clots and scars in the vicinity. Even a touch of the lesion by the endoscope may cause bleeding (Fig. 1). The ulcers are more readily recognized by narrow-band imaging cystoscopy.148 Occasionally ‘Hunner's ulcer’ is observed as a slightly reddish mucosal spot or only a convergent scar. We propose a new term, atypical Hunner's ulcer, for such small ambiguous lesions (Fig. 2). Atypical Hunner's ulcer may be overlooked without intentional search for the lesion. It usually undergoes ruptures and massive bleeding after hydrodistension and thus may be definitely diagnosed after hydrodistension. Importantly atypical ulcers should be treated by fulguration similarly for typical Hunner's ulcers. These lesions appear most commonly at the boundaries between the bladder dome and the posterior or lateral walls. It is important to watch the bladder mucosa from the early phase of filling, since Hunner's ulcer and especially atypical Hunner's ulcer may be obscured early after bladder distension. In patients without Hunner's ulcer or atypical Hunner's ulcer the entire mucosa appears to be fairly normal (non-ulcer type), although bladder capacity is reduced in most cases. Cystoscopy is required not only for the diagnosis of IC but for the differential diagnosis of ulcer type IC and non-ulcer type IC, which significantly differ in therapeutic responses.37,149,150

Figure 1.

Hunner's ulcer. Hunner's ulcer is a well-demarcated reddish mucosal lesion lacking in the normal capillary structure. It is occasionally associated with covering fibrin clots and scars in the vicinity. Even a touch of the lesion by the endoscope may cause bleeding.

Figure 2.

Atypical Hunner's ulcer. Atypical Hunner's ulcer is observed as a slightly reddish mucosal spot or only a convergent scar, and may be overlooked without careful observations. It usually undergoes ruptures and massive bleeding after hydrodistension, and thus is diagnosed after hydrodistension.

Hydrodistension

Hydrodistension is over-distending the bladder by hydrostatic pressure. It is usually carried out under general or spinal anesthesia (refer to treatment section for technical details). The procedure can be carried out using only mucosal anesthesia to confirm the diagnosis of IC at the office (diagnostic hydrodistension test). The diagnostic hydrodistension cannot distend the bladder fully due to inadequate anesthesia, thus the therapeutic efficacy is limited compared with that under adequate anesthesia. In most cases of IC the maximum bladder capacity is decreased (e.g. less than 500 mL). The ulcers, typical or atypical, sometimes rupture with distension, and massive or waterfall bleeding occurs on deflation from the affected sites. Non-ulcer type IC also shows mucosal bleeding after deflation, which varies in size, from a very limited area to the whole bladder, and in severity, from spotty bleeding from the bladder mucosa (glomerulations) to rainy bleeding. The findings are at present the sole objective and positive diagnosis bases for non-ulcer type IC.116 Despite the remaining doubt as to the sensitivity28 and specificity29,30 of the post-distension bleeding, the severity of bleeding had positive correlations with IC symptoms.151 Because of the importance of the cystoscopic findings, they should be recorded before and after distension in a standardized way (Figs 3,4).

Figure 3.

Symbols to be used for describing cystoscopic findings.

Figure 4.

Examples of cystoscopic findings at hydrodistension. Case 1: Hypervascular area was found on the right wall before hydrodistension. After hydrodistension, glomerulations in the posterior wall and rainy bleeding from the right wall were observed. The biopsy specimen was obtained from the left wall. Case 2: An ulcer extending from the right wall to the dome was found. On the corresponding left wall scars accompanied by the hypervascular area was observed. After hydrodistension, the ulcer turned into a rupture and started waterfall bleeding. Rupture and massive bleeding also observed in the scarred lesion (atypical Hunner's ulcer). Biopsy was taken from the retrotrigonal area.

Bladder biopsy

Bladder biopsy is not an essential part of diagnosis, as no specific histological findings for IC have been identified.139,152–154 Mast cell infiltration is often encountered, especially in ulcer-type IC. Its clinical significance would be ruling-out intraepithelial carcinoma and clarifying the histopathology of the patient.155 Biopsy is advised after hydrodistension to avoid risk of bladder rupture,155 although histological findings may be affected by the procedure.

Potassium sensitivity test

This test measures exacerbation of bladder pain after instilling potassium solution intravesically. IC patients tend to experience pain exacerbation to a greater extent, presumably due to increased permeability of the bladder mucosa to the solvent.156 The clinical value, however, would be limited due to high false-positive and false-negative rates and invasiveness of the procedure.157–160 Intravesical potassium may not simply act on urothelial sensory nerve endings; it may also stimulate detrusor muscle contraction.161

Urinary markers

Various kinds of urinary markers have been studied, among which the antiproliferative factor (APF) appears to be promising.162,163 Bladder distention altered urine APF activity and heparin-binding epidermal growth factor-like growth factor (HB-EGF) level toward normal.164 Increased levels of EGF and HB-EGF are implicated with inward potassium current.165 Other urinary markers included nitric oxide, histamine, methylhistamine, and interleukin-6 (IL-6).166,167 Four proteins that differed significantly between IC and controls were identified, with uromodulin and two kininogens higher for controls and inter-alpha-trypsin inhibitor heavy chain H4 higher for IC.168 Urinary concentration of neutrophile elastase increased in patients with pain and small bladder capacity.169 These markers are not necessarily precise predictors of ulcer and/or symptom severity.170

Exclusion of confusable diseases

Diseases to be excluded are listed in Table 1. It should be noted that IC coexists with these diseases.

Table 1.  Confusable diseases with interstitial cystitis
Bladder diseasesOveractive bladder, neurogenic bladder, bladder cancer, bladder calculus, radiation cystitis
Prostate and urethral diseasesProstatic hypertrophy, prostate cancer, urethral diverticulum, urethral stricture
Genitourinary infectionsBacterial cystitis, urethritis, prostatitis
Gynecologic diseasesEndometriosis, uterine myoma, vaginitis, climacteric disturbance
Other conditionsPolyuria, pelvic floor muscle pain

Recommended tests

Diagnostic tests were classified according to recommendation level (mandatory, recommended or optional) in Table 2.

Table 2.  Recommended tests for diagnosis of interstitial cystitis
MandatoryRecommendedOptional
  1. QOL, quality of life.

Clinical historyUrine cultureUltrasonography
Physical examinationsUrine cytologyUrodynamic study
UrinalysisSymptom scoresX-ray examination
QOL scoresPotassium test
Frequency-volume chartBiopsy
Residual urine measurement 
Prostate-specific antigen
Cystoscopy and/or hydrodistension

Treatment

Numerous therapeutic options are available for interstitial cystitis; however, most of them lack in high level evidence, leaving a few modalities as the recommended treatments.

The grade of recommendation for each treatment was determined by examining not only the level of evidence but the variability of efficacy, magnitude of efficacy, clinical applicability, morbidity and cost (Table 3), and is summarized in Table 4. A detailed and thorough consideration on the recent status is available elsewhere.171

Table 3.  The level of evidence and the grade of recommendation
  • Determined by the level of evidence, the variability of efficacy, magnitude of efficacy, clinical applicability, morbidity and cost.

Level of evidence
1Evidence obtained from multiple randomized controlled trials (RCTs)
2Evidence obtained from a single RCT or low quality RCTs
3Evidence obtained from non-randomized controlled studies
4Evidence obtained from observational studies or case series
5Evidence obtained from case studies or expert opinions
Grade of recommendation
AHighly recommended
BRecommended
CNo clear recommendation possible
DNot recommended
Table 4.  Treatments for interstitial cystitis
Treatment Grade of recommendationSuggested doses
  1. †Only for the treatments with grade of recommendation B and C. BCG, bacillus Calmette-Guerin; DMSO, dimethylsulfoxide; TENS, transcutaneous electric nerve stimulation; TUR, transurethral resection.

Conservative treatmentBehavior therapyB   
Stress reductionB   
Diet manipulationB   
Physical therapy C  
Hydrodistension B   
Medical treatmentPentosan polysulfateB  300 mg/day
AmitriptylineB  10–75 mg/day
Hydroxyzine C 25–75 mg/day
Suplatast tosilate C 300–600 mg/day
Cyclosporine A C 3 mg/kgBW/day
Steroid (predonisolone) C 5–25 mg/day
Cimetidine C 600 mg/day
Antibacterial agent  D 
L-arginine  D 
Intravesical instillation or bladder wall injectionDMSOB  50 mL of 50% solution
Heparin C 10 000 units
Hyaluronic acid C 40 mg
Chondroitin sulfate C 0.2–2%
Pentosan polysulfate C 300 mg
Oxybutynin C 0.01%
Lidocaine C 4%
Resiniferatoxin C 10–100 nM
Botulinum toxin C 100–200 IU
BCG  D 
Other treatmentsTENS C  
Neuromodulation C  
Acupuncture C  
Hyperbaric oxygen therapy C  
TURB  For ulcer-type
Cystectomy, Augmentation C Last resort

Conservative treatment

Grade of recommendation: B or C, Level of evidence for efficacy: 2 to 4

Behavioral therapy including timed voiding, controlled fluid intake, pelvic floor muscle training and bladder training improved symptoms in more than a half of the patients.172,173 Considering that mental stress is heightened in IC patients90 and it aggravates the symptoms, stress reduction such as exercise, bathing, shortening working hours or joining educational programs and patient support groups would be efficacious,94,174–176 which was confirmed by a randomized study.177 Support groups should be helpful, especially for lonely and less educated patients, and are available at http://www.ichelp.com/welcome.htm, http://www.tomonoki.org/ in Japan, or http://www.twica.org.tw in Taiwan. Dietary manipulation by avoiding acidic beverages, coffee, tea, soda, spicy food, artificial sweetener and alcohol may be beneficial.178–183 Each patient should be counseled to avoid the food that aggravates his or her symptoms.184–188 Physical therapy such as biofeedback and soft tissue massage relieves urinary frequency, bladder pain or coital pain probably through the relaxation of the pelvic floor muscles.189–195 To maximize the efficacy, however, the supervision by specialists may be required.

Medical treatment

Pentosan polysulfate

Grade of recommendation: B, Level of evidence for efficacy: 2  The glycosaminoglycan (GAG) layer is a non-specific protective mechanism of the bladder mucosa, and its deficiency is implicated with pathogenesis of IC. Pentosan polysulfate (PPS) is believed to repair the damaged GAG layer, but only 3–6% of orally administered PPS is excreted in the urine.196 Two open trials showed modest symptom improvement.197,198 The results of placebo-controlled double blind studies are conflicting,199–201 and there is no detectable dose-response relationship.202 PPS takes 3–6 months until the effect is seeable, and the effect is restricted to only about a quarter of patients. Initiating PPS treatment within 6 months of the diagnosis may be associated with greater improvement.203 Side effects are rare, including hair loss, diarrhea, nausea and headache in a long-term administration.201

Amitriptyline

Grade of recommendation: B, Level of evidence for efficacy: 2  Amitriptyline is expected to inhibit mast cell activity by blocking histamine H1 receptor and to modify pain transmission in the central nervous system by inhibiting serotonin and noradrenalin reuptake. Non-controlled studies demonstrated improvement of frequency and bladder pain in 26–73% of patients.204–207 In a prospective double blind study O'Leary & Sant's symptom score was reduced by more than 30% in 42% of the patients in the amitriptyline group, while it was only 13% in the placebo group.208 The efficacy was demonstrated in a long-term study.209 Adverse events were mild to moderate dry mouth and drowsiness. The response to tricyclic antidepressant therapy was related to the Arg16Gly polymorphism.210

Hydroxyzine

Grade of recommendation: C, Level of evidence for efficacy: 4  An experimental211 and some open-labeled studies have suggested efficacy in about half of patients211–215 with slight to moderate drowsiness as the adverse event. In a randomized comparative study, no significant difference was found between hydroxyzine and placebo, although a tendency towards a favorable effect of hydroxyzine was noted.216

Suplatast tosilate

Grade of recommendation: C, Level of evidence for efficacy: 4   Suplatast tosilate inhibits production of IgE, IL-4 and IL-5, and is efficacious for allergic diseases. A report from Japan suggested increase in bladder volume and symptomatic improvement in the majority of patients without serious side effects.217 No significant adverse event is known. In a mouse model it inhibited the release of histamine and tumor necrosis facto alpha (TNF-α) through a mechanism other than direct mast cell inhibition.218 It improves bladder function and pathological changes in hydrochloride (HCl)-induced cystitis rats.219

Cyclosporine A

Grade of recommendation: C, Level of evidence for efficacy: 2  The efficacy of cyclosporine was reported in open trials.220,221 In a randomized study comparing cyclosporine with pentosan polysulfate sodium, the response rate was 75% for cyclosporine compared with 19% for pentosan polysulfate sodium, and the response was related to a reduction of urinary EGF.222,223 Further studies were warranted, as adverse events are a concern.

Steroid

Grade of recommendation: C, Level of evidence for efficacy: 4   Efficacy of predonisolone for IC symptoms is suggested in a study, but hydrodistension was carried out simultaneously with predonisolone.224 Adverse events associated with long-term administration are a major concern.205 It may be indicated for ulcer type IC unresponsive to other treatments166,225 or IC related with autoimmune diseases.

Cimetidine

Grade of recommendation: C, Level of evidence for efficacy: 2   Cimetidine is a histamine H2-receptor antagonist. Three un-controlled studies indicated about 70% efficacy rate in IC.226–228 A randomized double blind study225 on 36 patients demonstrated a significant improvement in suprapubic pain and frequency compared with a placebo group; however, the detail of the study is unclear.229

Antibacterial agent

Grade of recommendation: D, Level of evidence for non-efficacy: 2   In a randomized placebo-controlled study, antibiotics including rifampin, doxycycline, erythromycin, metronidazole, clindamycin, amoxicillin and ciprofloxacin were shown to have no significant therapeutic effect over placebo.230 Adverse effects were more often in active arms.

L-arginine

Grade of recommendation: D, Level of evidence for non-efficacy: 1   L-arginine, a natural substrate of nitric oxide synthase (NOS), may re-activate NOS activity, which is suppressed in IC, and relieve symptoms.231 Another study, however, indicated no significant change in NO levels in the bladder and no improvement in symptoms.232 No significant effect was confirmed by subsequent double blind studies.233,234

Intravesical instillation or bladder wall injection

Dimethylsulfoxide

Grade of recommendation: B, Level of evidence for efficacy: 2   Dimethylsulfoxide (DMSO) is claimed to have anti-inflammatory, analgesic, muscle relaxant and collagenolytic effects. It prompted nitric oxide release from dorsal ganglion neurons and urinary bladder.235 In randomized236 and non-randomized237–240 studies, an approximately 80% improvement rate has been reported and the efficacy was favored for ulcer-type IC. Most patients recognized a garlic-like odor, and a few patients felt bladder spasm possibly due to mast cell degranulation.240 Periodic ophthalmic examinations are advisable as cataract has been reported in an animal study. Usually a solution of 50% DMSO diluted by physiological saline or distilled water is instilled into the bladder, and retained in the bladder for 10 to 20 min.241 The interval varies from a few times a week to every few months.

Heparin

Grade of recommendation: C, Level of evidence for efficacy: 4   Heparin is expected to function as glycosaminoglycan (GAG) layer on the bladder urothelium. More than a half of patients experienced symptom relief without significant adverse events in open trials.242–244 A randomized comparative study is necessary to obtain conclusive evidence. Instillation with lidocaine may be more efficacious.245

Hyaluronic acid

Grade of recommendation: C, Level of evidence for efficacy: 4   Hyaluronic acid, a glycoprotein, could repair the deficient GAG layer. Many reports suggested a long-lasting moderate efficacy with no significant toxicity.246–252 However, a recent randomized double blind study conducted in 2004 demonstrated no better efficacy than placebo (unpubl. data).

Chondroitin sulfate

Grade of recommendation: C, Level of evidence for efficacy: 4   Chondroitin sulfate, another glycoprotein, is known for its efficacy in open studies.253–255 Combined instillation of hyaluronic acid and chondroitin sulfate in refractory interstitial cystitis resulted in significant symptomatic improvement.256 Confirmatory studies are warranted.

Pentosan polysulfate

Grade of recommendation: C, Level of evidence for efficacy: 2   Pentosan polysulfate (PPS), instilled intravesically, may directly replenish the deficient GAG layer. A double-blind placebo-controlled study indicated its efficacy, although the sample number was so small (n = 20) and the magnitude of efficacy was limited.257 The combined use of intravesical and oral PPS is proposed as a therapeutic option.258

Oxybutynin

Grade of recommendation: C, Level of evidence for efficacy: 2  A single randomized trial indicated symptomatic resolution by intravesical instillation of oxybutynin in addition to bladder training.259

Lidocaine (with electromotive drug administration)

Grade of recommendation: C, Level of evidence for efficacy: 4   Lidocaine is a local anesthetic and relieves pain by blocking sensory nerves in the bladder, although pain relief lasts for a short time.260–263 Alkalization or electromotive drug administration (EMDA) of lidocaine is attempted to promote absorption.

Resiniferatoxin

Grade of recommendation: C, Level of evidence for efficacy: 4, non-efficacy: 2  Capsaicin, a C-fiber afferent neurotoxin, may alleviate the symptoms by desensitizing bladder afferents.264 Resiniferatoxin is more potent than capsaicin in desensitizing C-fibers with less irritation. Clinical efficacy was demonstrated clearly in studies of small sample size,26,265–267 but has not been confirmed in placebo-controlled studies.268,269 No particular toxicity was reported.269

Botulinum toxin

Grade of recommendation: C, Level of evidence for efficacy: 4   Botulinum toxin inhibits release of calcitonin gene-related peptide (CGRP) and substance P from afferent nerves and weakens pain response induced by acetic acid or cyclophosphamide in rats.270,271 Small studies indicated symptom relief in IC patients by botulinum toxin injection, single or repeated, into the bladder wall without significant adverse events.272–275 Further studies are warranted to confirm the promising efficacy.

Bacillus Calmette-Guerin

Grade of recommendation: D, Level of evidence for non-efficacy: 1   Bacillus Calmette-Guerin (BCG) is an immunomodulatory agent for the intravesical instillation therapy of bladder cancer, and was beneficial in an open study.276 An article demonstrated beneficial effects of BCG over placebo for IC symptoms.277 However, other studies including a randomized double blind study demonstrated no clinical benefit.278–281 Adverse events may be serious.

Hydrodistension

Grade of recommendation: B, Level of evidence for efficacy: 4 Hydrodistension has been the most common treatment for IC282,283 since the first report in 1930,284 although there has been no randomized comparative study. Most reports consistently indicated an approximately 50% efficacy rate, but the effect often persisted only for about 6 months.205,285–288 The presumed mechanism is that ischemia and metabolic acidosis induced by hydropressure degenerates afferent nerves, leading to reduced bladder pain and increased bladder capacity.176,286,289 Release of growth factors from the interstitum may also be involved. The procedure would be the most reliable intervention and indispensable for diagnosis of non-ulcer type IC (see Diagnosis section).

No standard method for hydrodistension or no significant difference in efficacy among the methods is known.290 Bladder rupture may occur as morbidity during hydrodistension.284,286,291 Prolonged distension may cause bladder necrosis.292 A suggested procedure is as follows.

  • 1General or spinal anesthesia at the Th6 level, preferably up to the Th4 level293
  • 2Inflate the bladder by physiologic saline by 80 cmH2O with continuous endoscopic observation for possible bladder ruptures. If the infused volume reaches 800–1000 mL before the intravesical pressure achieves 80 cmH2O, the infusion should be terminated.
  • 3After inflation of the bladder, maintain the pressure for a few minutes, drain the water, and observe the bladder mucosa for bleeding during the draining.
  • 4Procedures may be repeated, although the therapeutic significance of the repetition is unknown.
  • 5A urethral catheter can be placed in the bladder overnight.

Other treatments

Transcutaneous electric nerve stimulation

Grade of recommendation: C, Level of evidence for efficacy: 4   Transcutaneous electric nerve stimulation (TENS) is expected to eliminate pain by electrically stimulating peripheral sensory nerves in the skin.294,295 Some articles reported its efficacy for the treatment of ulcer-type IC.296,297 TENS is applicable at the outpatient clinic.

Electrostimulation including sacral nerve neuromodulation

Grade of recommendation: C, Level of evidence for efficacy: 2   Intermittent posterior tibial nerve stimulation somewhat improved less than half of patients.298 Sacral nerve neuromodulation is stimulation of the sacral root S3 or S4 by a permanent device to modulate afferent neural transmission, which results in pain relief, suppression of detrusor overactivity and stabilization of pelvic floor muscles.299,300 Multiple articles showed significant symptom improvement in open299–304 and blind studies.305 However, it requires a surgery for implantation and replacement of the device.

Acupuncture

Grade of recommendation: C, Level of evidence for efficacy: 3   Acupuncture is a traditional and relatively noninvasive therapy, although its precise mechanism of action is unclear.306 The efficacy of acupuncture for IC would be limited and transient, and repeated treatment will be required to maintain the effect.306,307 A large placebo effect is reported.308 It is an outpatient treatment with minimal morbidity.

Hyperbaric oxygen therapy

Grade of recommendation: C, Level of evidence for efficacy: 5, non-efficacy: 2  Hyperbaric oxygen therapy is demonstrated to be beneficial in an open study,309 but not statistically significant in a randomized, sham controlled, double-blind trial.310

Transurethral resection and transurethral coagulation

Grade of recommendation: B (for ulcer type only), Level of evidence for efficacy: 3  Endoscopic resection or fulguration of the bladder tissue diminishes inflammatory cells and hypersensitive sensory nerve endings, expectedly leading to symptomatic resolution. Transurethral resection (TUR) of the ulcer lesions eliminated symptoms for 1 year or longer in about half of patients,311–313 although it is less effective for non-ulcer IC. It is efficacious for patients who are refractory to hydrodistension without fulguration or have relapsed from the precedent TUR.314 Transurethral coagulation (TUC) using laser is an alternative to TUR and comparably effective.315–318 Bladder perforation, hemorrhage, urethral stricture and vesico-ureteral reflux (VUR) are known as the complications of these procedures.

Cystectomy, augmentation, urinary diversion

Grade of recommendation: C (last resort), Level of evidence for efficacy: 4  Surgical removal of the bladder is the last resort, when other treatments have failed to relieve the disabling symptoms.319,320 Supratrigonal cystectomy combined with augmentation cystoplasty using a bowel segment (ileal, ileocoecal, right colon, or sigmoid colon) is the most common procedure, achieving a significant symptomatic improvement.321–323 Results are apparently more favorable for patients with end-stage ulcer-type IC.324,325 Subtrigonal cystectomy would not be appropriate because of difficulties associated with ureteral or urethral anastomosis.326 Patients undergoing cystoplasty need a long-term follow-up for possible morbidities including hydronephrosis and adenocarcinoma in the intestinal portion.327 Total cystectomy and urinary diversion (continent urinary diversion, orthotopic neobladder or ileal conduit) is another option, although necessity of self catheterization or cosmetic concern should be taken into account.328 Pelvic pain or pouch pain may persist after augmentation and cystectomy.329–331 Sporadic reports indicate that urinary diversion with the bladder unresected improved the symptoms.139,332

Assessment of therapeutic effectiveness

The inclusion and efficacy criteria for clinical trials should be standardized to enhance the clinical research for interstitial cystitis.

New treatments for IC and hypersensitive bladder syndrome will be challenged for efficacy in the future. These diseases or conditions would need special consideration for the study design.333 To enhance the research process, the criteria for inclusion and efficacy assessment should be standardized.

Inclusion criteria

The criteria for enrolment (Table 5) are slight modification of the NIDDK inclusion criteria in 1987.10 Details of inclusion criteria, especially for target symptoms and their severity, should be determined to optimize the sensitivity to detect efficacy of the target treatment. Recent hydrodistension and bladder instillation are included in exclusion criteria in consideration of possible carry-over effects.

Table 5.  Inclusion/exclusion criteria for clinical research
  • Refer to Cystoscopy in the Diagnosis section of the text.

  • ‡Not included in the National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) criteria.

  • §

    NIDDK exclusion criteria deleted; age under 18, absence of urgency, capacity greater than 350 mL, involuntary bladder contractions by urodynamics, daytime frequency less than five times, nocturia less than two times, and symptoms relieved by antibiotics or anticholinergics.

  • Duration less than 9 months in NIDDK criteria.

Inclusion criteriaHunner's ulcer, atypical Hunner's ulcer or glomerulations on cystoscopy, AND lower urinary tract symptoms (urinary frequency, bladder hypersensitivity, urinary urgency, bladder pain)
Exclusion criteria§Duration less than 3 months, lower urinary tract infection in 3 months, hydrodistension in 3 months, bladder instillation in 1 month, neurogenic bladder, lower urinary tract calculi, genital herpes, bladder cancer, prostate cancer, urethral cancer, gynecologic cancer, urethral diverticulum, vaginitis, tuberculous cystitis, radiation cystitis and drug-induced cystitis

Efficacy criteria

Efficacy assessment method

There is no gold standard for efficacy assessment.333 The optimal method should be defined before starting study. The examples are given below.

  • • Aggregated or composite symptom scores
  • • Individual symptom scores
  • • Variables of voiding recording (i.e. voiding frequency and single voided volume)
  • • QOL scores
  • • Global response assessment by patients' subjective impressions (i.e. Table 6134)
Table 6.  An example of a questionnaire for overall improvement by patients' subjective impressions
Have your bladder symptoms been improved or worsened by the treatment?
Choose one statement which best fits to your impression.
1. Markedly improved
2. Moderately improved
3. Slightly improved
4. No change
5. Slightly worsened
6. Moderately worsened
7. Markedly worsened

Potential factors that may affect the efficacy assessment

  • • Symptom severity
  • • Presence or absence of bladder pain, and its intensity
  • • Bladder capacity
  • • Presence or absence of an ulcer (ulcer type, non-ulcer type)149
  • • Gender
  • • Age

Other considerations

  • • A placebo-controlled (or standard-treatment-controlled) double-blind study is highly recommended for pharmaceutical therapy because of a high placebo effect.
  • • Efficacy assessment should be carried out at 3 months after intervention. Assessment of long-term efficacy (e.g. at 6 months or 12 months) is also recommended.

Clinical algorithm

The algorithm is constructed to guide the care providers to the proper management in the diagnosis and treatment of patients with hypersensitive bladder syndrome (Fig. 5).

Figure 5.

Clinical algorithm for hypersensitive bladder syndrome. This algorithm is for subjects presenting with hypersensitive bladder symptom syndrome, which is defined as bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain. The basic evaluation consists of the mandatory evaluation (history taking, physical findings, and urinalysis), recommended evaluation (urine culture, urine cytology, symptom scores, quality of life [QOL] scores, frequency-volume chart, residual urine measurement, and prostate-specific antigen), or optional evaluation (urodynamic tests, imaging tests, and potassium test). After basic evaluation, one may follow three choices. (A) When interstitial cystitis is highly likely, hydrodistension under adequate anesthesia should be considered. Less invasive treatments may be administered without definite diagnosis, or attempted concomitantly with hydrodistension. (B) When interstitial cystitis is likely or no other diseases are identified, three choices are available. First, empirical therapy with less invasive treatments for interstitial cystitis (conservative, medical or instillation treatments) are attempted without a definite diagnosis, and the second or third choice is to be considered when the empirical therapy fails (a). Second, one can directly proceed to hydrodistension under adequate anesthesia (b: see below). Third, cystoscopy is considered to identify Hunner's ulcer or other pathologies in the bladder. If no abnormality is found, a diagnostic hydrodistension test can be carried out. The test is an office-base diagnostic procedure to confirm the glomerulations (spotty bleeding from the bladder mucosa) by incomplete bladder distension under mucosal anesthesia (c). (C) When interstitial cystitis is unlikely or other diseases are identified, appropriate treatments should be initiated. Other diseases that may cause hypersensitive bladder syndrome include urinary calculi, bladder cancer, prostate cancer, urethral cancer, bacterial cystitis, prostatitis, urethritis, neurogenic bladder, overactive bladder, benign prostatic hyperplasia, urethral stricture, urethral diverticulum, polyuria, and so on. Should the treatment provide no sufficient improvement, consider re-evaluation for the accurate diagnosis. Hydrodistension under general or spinal anesthesia not only confirms the diagnosis of interstitial cystitis but provides therapeutic benefit to the patients. Hunner's ulcers or atypical Hunner's ulcers, if present, should be endoscopically coagulated or resected. When sufficient improvement cannot be achieved or the symptoms recurred after initial treatments, combined or repeated treatments should be considered. Cystectomy is the last resort.

Ancillary