International Journal of Urology (2016) 23, 542--549 doi: 10.1111/iju.

13118

Guideline

Clinical guidelines for interstitial cystitis and hypersensitive bladder

updated in 2015
Yukio Homma,1 Tomohiro Ueda,2 Hikaru Tomoe,3 Alex TL Lin,4 Hann-Chorng Kuo,5 Ming-Huei Lee,6
Seung-June Oh,7 Joon Chul Kim8 and Kyu-Sung Lee9
1
Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, 2Department of Urology, Ueda Clinic,
Kyoto, 3Department of Urology, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan, 4Department of Urology,
National Yang Ming University and Taipei Veterans General Hospital, Taipei, 5Department of Urology, Buddhist Tzu Chi General
Hospital and School of Medicine, Tzu Chi University, Hualien, 6Department of Urology, Feng-Yuan Hospital, Taichung, Taiwan,
7
Department of Urology, Seoul National University, Seoul, 8Department of Urology, The Catholic University of Korea, Seoul, and
9
Department of Urology, Sung Kyun Kwan University School of Medicine, Seoul, Korea

Abbreviations & Acronyms Abstract: Clinical guidelines for interstitial cystitis and hypersensitive bladder have
APF = antiproliferative been updated as of 2015. The guidelines define interstitial cystitis by the presence of
factor hypersensitive bladder symptoms (discomfort, pressure or pain in the bladder usually
BCG = bacillus Calmette– associated with urinary frequency and nocturia) and bladder pathology, after excluding
Gu
erin other diseases explaining symptoms. Interstitial cystitis is further classified by bladder
BPS = bladder pain pathology; either Hunner type interstitial cystitis with Hunner lesions or non-Hunner type
syndrome interstitial cystitis with mucosal bleeding after distension in the absence of Hunner
DMSO = dimethyl sulfoxide lesions. Hypersensitive bladder refers to a condition, where hypersensitive bladder
HSB = hypersensitive symptoms are present, but bladder pathology or other explainable diseases are
bladder unproven. Interstitial cystitis and hypersensitive bladder severely affect patients’ quality
IC = interstitial cystitis of life as a result of disabling symptoms and/or comorbidities. Reported prevalence
MBAD = mucosal bleeding suggestive of these disorders varies greatly from 0.01% to >6%. Pathophysiology would
after distension be an interaction of multiple factors including urothelial dysfunction, inflammation, neural
NGF = nerve growth factor hyperactivity, exogenous substances and extrabladder disorders. Definite diagnosis of
PBS = painful bladder interstitial cystitis and hypersensitive bladder requires cystoscopy with or without
syndrome hydrodistension. Most of the therapeutic options lack a high level of evidence, leaving a
QOL = quality of life few as recommended therapeutic options.
TENS = transcutaneous
electric nerve stimulation
Key words: guidelines, Hunner lesions, hypersensitive bladder, interstitial cystitis.

Correspondence: Yukio
Homma M.D., Department of Introduction
Urology, Graduate School of Clinical guidelines are to be revised regularly by incorporating scientific progress. We have
Medicine, The University of summarized the advances in the basic science and clinical management of interstitial cystitis
Tokyo, 7-3-1 Hongo, Bunkyo- during these 6 years since the last publication. The readers are kindly advised to look at the
ku, Tokyo 113-8655, Japan. previous guidelines; most of the previous descriptions and references are not repeated for the
Email: homma-uro@umin.ac.jp sake of conciseness.1
Received 7 March 2016;
accepted 5 April 2016. Methods
Online publication 24 May 2016
The previous guidelines for interstitial cystitis and hypersensitive bladder syndrome were
updated using materials identified by the PubMed database published from 2008 to the end of
2015 including e-publications.1 Guidelines issued by the American Urological Association or
European Society for the Study of IC were also counselled.2–4

Definition
There is no widely accepted definition of IC and related conditions. A lack of definition has
incurred confusion by creating many terms: PBS, BPS, IC/PBS (PBS/IC) and IC/BPS (BPS/IC)
are examples.2–4 In reality, however, these terms are used interchangeably without distinction.
Another source of confusion is “pain” in PBS and BPS; a significant proportion of IC patients
do not complain of pain. The symptoms could be rather characterized as “hypersensitive,” as

542 © 2016 The Japanese Urological Association

 Clinical guidelines for IC and HSB

urothelium is a sophisticated sensory tissue,5 and sensory of NGF leads to neuronal hyperinnervation, nervous hyperac-
hyperactivity is implicated in bladder disorders including IC.6,7 tivity and bladder dysfunction.31 Urinary NGF levels are clo-
Thus, in the current guidelines, we used the previous definition sely related to pain score and therapeutic responses.32
with slight modification (Table 1). IC is defined by hypersensi- Systemic or central neural hyperactivity is indicated by
tive bladder symptoms and bladder pathology after excluding increased sympathetic nerve activity,33–36 segmental hyperal-
other diseases explaining symptoms. Bladder pathology is gesia with spinal sensitization,37 or increased mental stress
either a Hunner lesion or MBAD. The condition with hyper- and multiple sensitivities38 in IC patients.
sensitive bladder symptoms, but no proven bladder pathology
or other explainable diseases, is designated as HSB.8
Impaired microcirculation
IC bladders show increased expression of angiogenic growth
Pathophysiology factors and apoptosis of endothelial cells. Increased and dys-
Pathophysiology of IC and HSB would be a complex of mul- regulated angiogenesis is implicated with mucosal bleeding
tiple factors. after distension.39,40 Intravesical onabotulinumtoxin A injec-
tions downregulate vascular endothelial growth factors.41
Urothelial dysfunction
Exogenous substances and infection
Alterations of urothelial differentiation and homeostasis are
shown by denudation of the epithelium,9 low expression of Consumption of specific diet triggers symptom worsening.42
interleukin-8,10 increased levels of apoptosis with decreased Chronic ketamine abuse causes bladder inflammation associ-
proliferation,11,12 or abnormal expression of APF, uroplakin, ated with immunological hypersensitivity.43 Urine alkalization
chondroitin sulfate and tight junctional proteins. Dysregulated by citrate improved HSB symptoms.44
urothelium can result in increased permeability, generating Association of IC and infection of a microorganism or
hypersensitive bladder symptoms.13 In turn, glycosaminogly- virus has not been confirmed, although women with recurrent
can substitutes or APF antagonists normalize permeability.14,15 urinary tract infection have increased urothelial cell apoptosis,
Hypersensitive symptoms in recurrent urinary tract infection increased mast cell count and lower E-cadherin, which could
might be explained by increased urothelial cell apoptosis.16 cause the hypersensitivity symptoms in these women.16

Inflammation Extrabladder disorders

IC patients have high urinary concentrations of immunoglobu- IC patients have a higher risk for irritable bowel syndrome,
lin and inflammatory markers,17–20 or high serum levels of C- fibromyalgia, general fatigue, functional somatic syndrome,
reactive protein, NGF and pro-inflammatory cytokines.21–24 comorbid neurological diseases, rheumatological diseases and
Bladders with Hunner type IC show diffuse and intense inflam- mental illnesses.33,45–49 Neuronal cross-talk with pelvic
mation9 and overexpression of pro-inflammatory genes.6,7,25–27 organs might exaggerate bladder symptoms; patients have a
Light-chain restriction in infiltrated plasma cells suggests higher risk for prior hysterectomy;46 pelvic myofascial pain is
involvement of specific immunological reactions.9 Bladder implicated with therapeutic response.50
inflammation is likely to induce afferent nerve overactivity.28
Epidemiology
Neural hyperactivity
The known prevalence of IC or conditions suggestive of IC
IC bladders show upregulation of TRPV1,7,29 or increased ranged from 0.01% to 2.3%, with an approximately fivefold
release of NGF, ATP and prostaglandins.30 Overexpression female dominance.1 The RAND Interstitial Cystitis Epidemiol-
ogy study found approximately 2.70–6.53% of women met the
high specificity and high sensitivity IC symptom criteria.51 In
Table 1 Definition of IC and HSB Japan, 1.0% of the general population experienced bladder pain
Criteria
every day, and the actual number of IC and HSB patients under
medical care was estimated as approximately 4500 (0.004%).52
IC 1. Hypersensitive bladder symptoms†
In Korea, a population-based cross-sectional survey showed
2. Bladder pathology‡
3. No other diseases explaining symptoms
the prevalence of IC as 0.26% in women.53 The prevalence in
Subtype of IC Hunner type IC: IC with Hunner lesions Taiwan was 22 per 100 000 people (0.022%).54 IC patients
Non-Hunner type IC: IC with MBAD in the absence of have a higher risk for prior non-bladder surgery,55 or non-blad-
Hunner lesions der pain and hypersensitive syndromes.33,45–49
HSB 1. Hypersensitive bladder symptoms
2. No proven bladder pathology or other
explainable diseases Diagnosis
†Discomfort, pressure or pain in the bladder usually associated with The diagnosis of IC is made by the presence of symptoms
urinary frequency and nocturia. ‡Hunner lesions or MBAD. and bladder pathology (Table 1). Symptomatic patients with-
out bladder pathology are diagnosed as HSB.8

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Y HOMMA ET AL.

thorough observation, which should be recorded in a stan-

Symptoms and QOL
dardized way.1 Hunner lesions sometimes rupture during dis-
Common symptoms of IC and HSB are discomfort, pressure tension, and waterfall bleeding occurs on deflation. A bladder
or pain in the bladder usually associated with urinary fre- that appears normal before distension might undergo MBAD
quency and nocturia. These symptoms are collectively called during emptying (Fig. 2). MBAD and glomerulations are not
HSB symptoms. Bladder pain would be the most typical identical; MBAD donates mucosal bleeding seen during the
symptom. However, a substantial portion of patients do not first emptying, whereas glomerulations describe spotty sub-
complain of pain. Symptoms are susceptible to dietary, envi- mucosal hemorrhages found at the second filling.62 A recent
ronmental and mental stress, with variable remissions and review article has provided no convincing evidence that
exacerbations.56 Many symptom assessment tools are avail- glomerulations should be included in the diagnosis or pheno-
able, although a single specific questionnaire cannot offer typing of IC.62 However, MBAD is an obvious abnormal
complete assessment.57 The QOL is negatively affected by endoscopic finding, and would represent some bladder
HSB symptoms; patients had lower economic status, painful pathology.
sex and sleep disorders.58 Bladder pain, depressive symp-
toms, physical disability, comorbidities and less work partici-
Bladder biopsy
pation were related to each other.59,60
Bladder biopsy might not be essential for diagnosis. How-
ever, Hunner type IC shows epithelial denudation and dense
Clinical examinations
inflammatory infiltrates in the bladder, which are totally dif-
Urinalysis usually showed no abnormality. Urinary diaries ferent from non-Hunner type IC or HSB.9
showed increased urinary frequency and constant small
voided volumes all day.61
Biomarkers
Numerous diagnostic biomarkers are explored including APF,
Cystoscopy
urinary18,19 or serum24 NGF, and urinary or serum pro-
Cystoscopy is required for the diagnosis of Hunner type IC. inflammatory cytokines or chemokines.22 An intratissue
A Hunner lesion is recognized as a reddish mucosal lesion increase in chemokines or receptors related to pro-nociceptive
lacking in the normal capillary structure associated with con- inflammatory reactions has been reported.7 However, there
verging vessels, covering fibrin clots or scars in the vicinity are no universally accepted biomarkers.63
(Fig. 1). A highly variable proportion of patients with Hun-
ner lesions among hospitals suggest inconsistent diagnostic
Other diseases to be excluded
criteria for the lesions.52 It is crucially important to watch
the bladder mucosa from the early phase of filling, as Hun- Many diseases can cause HSB symptoms thus to be
ner lesions might be obscured soon after bladder distension. excluded. The examples are bladder diseases (overactive
The lesions are more readily recognized by narrow-band bladder, neurogenic bladder, bladder cancer, bladder calcu-
imaging cystoscopy. lus, radiation cystitis, chemical cystitis, ketamine-related cys-
titis), prostate and urethral diseases (benign prostatic
hyperplasia, prostate cancer, urethral cancer, urethral divertic-
Hydrodistension
ulum, urethral stricture), genitourinary infections (bacterial
Hydrodistension is not simple overdistension of the bladder cystitis, urethritis, prostatitis), gynecological diseases (gyne-
by hydrostatic pressure, but inclusive of careful observation cological malignancies, endometriosis, uterine myoma,
of the bladder mucosa during distension and emptying. It is vaginitis, climacteric disturbance) or other conditions (poly-
preferably carried out under general or spinal anesthesia for uria, urinary stones).

(a) (b)

Fig. 1 Hunner lesion. (a) A Hunner lesion is a

reddish mucosal lesion lacking in the normal
capillary structure. It is often associated with
converging vessels, covering fibrin clots and scars
in the vicinity. (b) The lesions are more readily
recognized by narrow-band imaging cystoscopy.

544 © 2016 The Japanese Urological Association

 Clinical guidelines for IC and HSB

(a) (b)

Fig. 2 MBAD. The (a) apparently normal bladder

mucosa shows (b) intravesical rainy bleeding
during bladder emptying after distension.

Recommended tests Amitriptyline

Diagnostic tests were classified according to recommendation Amitriptyline is expected to inhibit mast cell activity and to
level (Table 2). modify pain transmission in the central nervous system.
Uncontrolled or double-blind studies showed modest efficacy.
However, a recent randomized double-blind study showed no
Treatment statistically significant efficacy over a placebo.70 The
The grade of recommendation as previously determined is response rate was significantly higher (66%) than the placebo
shown in Table 3.1 Therapies with no major progress during (47%) in a subgroup who achieved a drug dose of at least
these 7 years were not mentioned in the text. 50 mg.
Cyclosporine A
Conservative treatment
The efficacy of cyclosporine was shown in open trials and a
Dietary modification by avoiding acidic foods, high-potas- randomized study. A retrospective review showed a high suc-
sium foods, coffee, tea, soda, spicy foods, artificial sweetener cess rate (68%) for patients with Hunner lesions compared
and alcohol is beneficial.64 Behavioral therapy with controlled with those without (30%).71 Close monitoring is required, as
fluid intake and bladder training improve frequency–ur- adverse events can be serious.
gency.65 A randomized study showed the efficacy of physical
Steroid
therapy with myofascial therapy in improving pelvic pain.66
The guided imagery technique also helps to reduce pelvic Oral steroid might be indicated for Hunner type IC resistant
floor tonicity and pain. Psychological support from a spouse to other treatments or IC accompanied by autoimmune dis-
or patient support groups is an indispensable component of eases, such as systemic lupus erythematosus and Sj€ ogren’s
IC therapy.67 Management using the biopsychosocial model syndrome.72 Adverse events might be associated in long-term
was effective in recovering QOL impairment.67,68 treatment.
Citrate
Medical treatment
Alkalization of urine by citrate improved HSB symptoms
Pentosan polysulfate
and QOL impairment with an increase in single voided
Pentosan polysulfate can improve symptoms by repairing the volume.44
damaged glycosaminoglycan layer of the urothelium. How-
ever, the results of placebo-controlled double blind studies Intravesical instillation or bladder wall
are conflicting. A recent double-blind, randomized, placebo injection
study showed no statistically significant improvement com-
DMSO
pared with a placebo.69
Randomized and non-randomized studies showed some effi-
cacy.73
Table 2 Clinical tests for diagnosis
Heparin
Mandatory Clinical history, physical examinations, urinalysis
Recommended Urine culture, urine cytology, symptom scores, Previous and recent open studies showed efficacy of heparin
QOL scores, frequency–volume chart, or heparin combined with alkalized lidocaine.74,75
residual urine measurement, prostate-specific antigen,
cystoscopy with or without hydrodistension Hyaluronic acid
Optional Urodynamic study, pelvic imaging tests, bladder biopsy
Many reports showed a long-lasting moderate efficacy with
no significant toxicity.76

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Y HOMMA ET AL.

Table 3 Treatments for IC and HDB

Grade of recommendation Suggested doses†

Treatment (level of evidence) or indication
Conservative treatment B or C (2–4)
Medical treatment Pentosan polysulfate C/B (2, 2)‡ 300 mg/day
Amitriptyline B/C (2, 2) 10–75 mg/day
Hydroxyzine§ C (4) 25–75 mg/day
Suplatast tosilate§ C (4) 300–600 mg/day
Cyclosporine A C (2) 3 mg/kgBW/day
Steroid (prednisolone) C (4) 5–25 mg/day
Cimetidine§ C (2) 600 mg/day
Antibacterial agent§ D (2)
L-arginine§ D (4, 2)
Citrate C (4) 853 mg/day
Intravesical instillation or DMSO B (2) 50 mL of 50% solution
bladder wall injection Heparin C (4) 10 000 units
Hyaluronic acid C (4) 40 mg
Chondroitin sulfate C (4, 2) 0.2–2%
Pentosan polysulfate§ C (2) 300 mg
Oxybutynin§ C (2) 0.01%
Lidocaine C (4) 4%
Resiniferatoxin§ C (4, 2) 10–100 nmol/L
Botulinum toxin B (2) 100–200 IU
Steroid C (4) 40 mg/mL 10 mL
BCG§ D (2, 2)
Hydrodistension B/C (4)
Other treatments TENS§ C (3)
Neuromodulation B (2)
Acupuncture C (3, 3)
Hyperbaric oxygen C (4, 2)
Fulguration B (3) Hunner type IC only
Cystectomy or augmentation C (4) Last resort

†Only for the treatments with grade of recommendation B and C. ‡Level of evidence for efficacy, level of evidence for non-efficacy. §No major progress during
these 6 years.

Chondroitin sulfate Hydrodistension

Single or combined instillation with hyaluronic acid showed Most reports showed an approximately 50% efficacy rate and
symptom improvement. However, it was negated in a ran- a few-month efficacy persistence. The putative mechanism
domized double-blind controlled study.77 for efficacy includes degeneration of afferent nerves, anti-
inflammatory effect or reduction of nerve growth factor.32 A
Lidocaine study identified concomitant lumbar spinal stenosis and irrita-
Lidocaine can relieve pain by blocking sensory nerves for a ble bowel syndrome as predictors for poor outcomes.83 Sug-
short time. Alkalization of lidocaine is believed to promote gested procedures for hydrodistension were described
absorption.74 previously.1
Botulinum toxin
Other treatments
Single-arm or randomized studies showed symptom relief by
Electrostimulation
botulinum toxin injection, single or repeated, into the bladder
wall.78,79 The average duration of effect was approximately The efficacy of permanent sacral nerve neuromodulation was
6 months, and repeated injections seem to be necessary. It is shown in many studies, and confirmed in a long-term obser-
uncertain whether the presence of Hunner lesions affects the vation.84,85 Intermittent posterior tibial nerve stimulation or
efficacy of injection.80,81 pudendal nerve stimulation also showed efficacy.
Steroid Acupuncture
Submucosal injections of a corticosteroid in and around Hun- A large placebo effect, and contradictory results with limited
ner lesions offered significant symptomatic improvement.82 and temporary efficacy were reported.86

546 © 2016 The Japanese Urological Association

 Clinical guidelines for IC and HSB

Hypersensitive bladder symptoms

Basic evaluation

Hypersensitive bladder (HSB)

Conservative or medical treatment Other diseases

Not improved Cystoscopy (+Hydrodistension)

Treatment
IC (Hunner or non-Hunner) or non-IC HSB

Hydrodistension, fulguration of Hunner lesion

Not improved

Repeated or combined treatment with instillation, injection, and electrostimulation,

or cystectomy

Fig. 3 Clinical algorithm for hypersensitive bladder symptoms. This algorithm is for patients presenting with HSB symptoms (discomfort, pressure or pain in the
bladder usually associated with urinary frequency and nocturia). The basic evaluation consists of the mandatory evaluation (history taking, physical findings and uri-
nalysis), and recommended or optional tests (see Table 2). When other diseases are identified, appropriate treatments should be initiated. When IC or HSB is likely,
cystoscopy with or without hydrodistension is recommended to make a definite diagnosis. Alternatively, conservative or medical treatment can be empirically initi-
ated, with cystoscopy carried out when the therapy fails. Hydrodistension is preferentially carried out under spinal or general anesthesia to confirm mucosal bleed-
ing after distension. If Hunner lesions are found on cystoscopy, fulguration of lesions is indicated. In any case, conservative or medical treatment should be
considered concurrently. When sufficient improvement cannot be achieved, consider re-evaluation, repeated treatment or combined treatments with bladder instil-
lation, bladder injection and electrostimulation. Cystectomy is the last resort.

Hyperbaric oxygen therapy Assessment of therapeutic

The efficacy of hyperbaric oxygen was not statistically sig-
effectiveness
nificant in a randomized double-blind trial. However, it Clinical studies for IC and HSB require special consideration
seems to be beneficial in some patients, such as those for the study design, inclusion criteria and outcome measures,
with Hunner type IC87 or those after DMSO instillation as described previously.1 Outcomes of medical treatment
therapy.88 might not be affected by cystoscopic findings.93
Transurethral fulguration
Clinical algorithm
Many studies reported the efficacy of transurethral electro- or
laser fulguration of the Hunner lesions. Recent studies con- The algorism is constructed for the proper management of
firmed the efficacy, and found pain relief persisted for a few patients presenting HSB symptoms (Fig. 3).
months to 2 years post-treatment.83,89–91
Cystectomy, augmentation and urinary diversion Conflict of interest
Partial or complete cystectomy and bladder augmentation None declared.
with or without urinary diversion would be the last resort for
intractable cases, who are resistant to the aforementioned
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