cistitis insterticial
DESCRIPTION
TRANSCRIPT
American Urological Association Education and Research Inc.
2008 Annual Meeting, Orlando, FL May 17-22, 2008
Sponsored by: The American Urological Association Education and Research, Inc.
COURSE 93 IC
FACULTY
Philip M. Hanno, M.D., M.P.H Course Director
David A. Burks, M.D.
Interstitial Cystitis/Painful Bladder Syndrome: A Primer and an Update
Tuesday, May 20, 2008 1:45 - 3:15 p.m.
Tuesday, May 20, 2008 1:45 - 3:15 p.m.
Interstitial Cystitis/Painful Bladder Syndrome: A Primer and an Update
COURSE 93 IC
FACULTY
Philip M. Hanno, M.D., M.P.H Course Director
David A. Burks, M.D.
American Urological Association Education and Research Inc.
2008 Annual Meeting, Orlando, FL May 17-22, 2008
Sponsored by: The American Urological Association Education and Research, Inc.
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2008 AUA Annual Meeting
93 IC Interstitial Cystitis / Painful Bladder Syndrome – A Primer and an Update 5/20/2008 1:45 - 3:15 p.m.
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Bladder Pain Syndrome / Interstitial Cystitis A Primer and an Update 2008
Philip Hanno
David Burks
Agenda: 0-5 minutes: Classification of Chronic Pain Syndromes 5-15 minutes: Definitions 15-20 minutes: Epidemiology 20-25 minutes: Etiology 25-45 minutes: Practical Diagnosis 45-60 minutes: Treatment and Management 60-70 minutes: What’s New? What’s Next?? 70-90 minutes: Questions and Discussion
1
Bladder Pain Syndrome/Interstitial Cystitis
Philip Hanno MD, MPHProfessor of Urology
University of Pennsylvania
David Burks MD,Vattikuti Urology Institute,
Henry Ford Hospital, Detroit
Name in historyTic doloureux of the bladder 1836Interstitial cystitis 1878Cystitis parenchymatosa 1907Hunner’s ulcer 1915
Panmural ulcerative cystitis 1920Urethral syndrome 1949 Painful bladder syndrome 1951 (Bourke), 2002 ICSBladder pain syndrome 2006 (ESSIC, PUGO)
What’s In A Name?
The Analects of Confucius, Book 13, Verse 3 (James R. Ware, translated in 1980.)
Tsze-lu said, “The ruler of Wei has been waiting for you, in order with you to administer the government. What will you consider the first thing to be done?”
The Master replied, “What is necessary is to rectify names.” “So! indeed!” said Tsze-lu. “You are wide of the mark! Why must there be such rectification?”
The Master said, “How uncultivated you are, Yu! A superior man, in regard to what he does not know, shows a cautious reserve
“If names be not correct, language is not in accordance with the truth of things. If language be not in accordance with the truth of things, affairs cannot be carried on to success
Why is there a problem?
What Seems Simple and Obvious May Not Really Be
Bladder Pain / Frequency / Urgency Frequency dependent upon drinking habits and perspiration; absolute # may not be meaningfulUrgency dependent upon definition: the complaint of a sudden compelling desire to pass urine which is difficult to defer (possibly) because of fear of incontinence (no); Consider term “persistent urge”Site of pain, source of pain can be difficult for patient or clinician to determine
2
Painful Bladder Syndrome/IC does not stand alone
Painful BladderShould Fit In
Pharmacogenomics 2006:7:521-528
Demitrack
vulvodynia
migraine
EAU Classification
Chronic Pelvic Pain Syndrome
Poorly characterized conditions Well characterized conditions
urological
gynecological
anorectal
neurological
muscular
Other
Feb 2003, Fall, Baranowski, et.al.
Well-Defined Conditions
InfectiveProstatitis
InfectiveEpididymo-
Orchitis
InfectiveUrethritis
InfectiveCystitis
Urologic
NIH Type1 and 2
Poorly Characterized Entities
Scrotal Pain
Penile Pain
Urethral Pain
Prostate PainNIH type 3
PBS/IC
Urological
Testicular pain synPost vasectomyEpididymal pain syn
Poorly Categorized Entities
VulvarPain Syn
Vaginal Pain Syn
Endometriosis Assoc Pain
GYN
3
Definition is a ProblemHow do we arrive at a clinical definition? What is/are the best definition(s) to be used in epidemiologic studies What are the best methods to develop such definitionsWhat can we learn about PBS/IC from the different epidemiologic studies?
The world priorTo NIDDKCriteria
“A hole in the air”Tage Hald
Endoscopic DefinitionHunner’s definition of Interstitial Cystitis
“…a peculiar form of bladder ulceration whose diagnosis depends ultimately on its resistance to all ordinary forms of treatment” in patients with frequency and bladder symptoms (spasms).”
Hunner, GL, Boston Medical and Surgical Journal, 172:660, 1917
Clinical Definition: The Aunt Minnie (hard to describe but you know her when you see her)We have all met, at one time or another, patients who suffer chronically from their bladder; and we mean the ones who are distressed, not only periodically but constantly, having to urinate often, at all moments of the day and of the night, and suffering pains every time they void. Bourke, 1951
Symptoms & Endoscopic Appearance DefinitionMessing and Stamey:
Nonspecific and highly subjective symptoms of around the clock frequency, urgency, and pain somewhat relieved by voiding when associated with glomerulations upon bladder distention under anesthesia
Urology, 12:381, 1978
NIDDK CriteriaTo define research parameters of IC so that clinical and basic research findings would have a common basis for comparisonNot meant to be de facto definition for the clinician
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Revised NIDDK CriteriaPain associated with the bladder orurinary urgency and glomerulations orHunner’s ulcer on cystoscopy under anesthesiaLong list of exclusions of other disorders that might give rise to symptoms9 month symptom duration8 voids per day and nocturia X 1 minimumLess than 350 cc awake bladder capacity
Interstitial Cystitis (Hanno, Wein, Staskin, Krane (eds); Springer Verlag 1990)
NIDDK IC Database Definition for Entry Criteria
Broaden criteria to attempt to validate NIDDK criteriaInclude all “IC-like” patientsUnexplained urgency or frequency (7 voids or more a day), or pelvic pain of at least 6 months durationNo requirement for cystoscopy or endoscopic findings
Urology, 49:5A, 64-75, 1997
NIDDK IC Database Findings
0102030405060708090
notmeetingcriteria
meetingcriteria
PatientsAgreed To Have ICBy ExpertClinicians
Hanno, J. Urol. 1999
424 patients with urgency or pain or frequency > 6 months
Criteria Fulfilled Mission
Criteria MissedClinical IC Patients
Laboratory Definition:Antiproliferative Factor
Unique protein found only in urine of IC patientsDiscovered by Sue Keay, U of MDIn search for infectious etiology of IC, cell cultures showed differences between IC bladder and control cellsSlow growth rate of IC cells led to discovery of antiproliferative factorAPF is expressed solely in the bladder epithelium of IC patients with no expression evident in normal human bladder epithelial cells
Initial studies with 200 IC patients and 300 controls demonstrated specificity and sensitivityAPF activity and altered levels of HB-EGF and EGF previously identified in IC urine are relatedAPF upregulates bladder epithelial cell production of EGF and down-regulates production of HB-EGF in vitro
O
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Not ready for prime time
Pathologic Definition
Nonulcerative IC Hunner’s ulcerNerve hypertrophyDetrusor mastocytosis
Excludes tissue specific diagnoses only, no pathognomonic findings
5
Provocative Testing Definition: Positive Potassium Test
Intravesical potassium sensitivity testing (Parsons) uses pharmacologic .4N, not physiologic concentrations+ test may indicate increased permeability and/or increased neural acuity
Obstet Gynecol, 98:127, 2001Urology, 60:573, 2002
J Urol, 168:1054, 2002Urology, 59:329, 2002
Sensitivity of Potassium TestGold Standard for Defining Unequivocal IC is NIDDK CriteriaUp to 25% of NIDDK positive patients have a negative potassium test
Parsons, CL: J Urol., 1862-67, 1998
Specificity of Potassium Test36% false positive in asymptomatic men25% false positive in OABUp to 100% false positive in UTI and Radiation Cystitis33% positive in Turkish ♀ textile workers
Yilmaz, J Urol, 172:548, 2004
Parsons, J Urol 1862-67, 1998Parsons, Neurourol & Urodyn 13:515, 1994
Urol Int 2008;80:52–56Sahinkanat
Specificity of potassium test50-84% false positive males with CPPS23% positive in unselected women in US
Parsons, J Urol 168:1054, 2002Parsons, Urol, 60:1054, 2002Yilmaz J Urol 172:548, 2004
ICS Definitions OAB: Urgency with or without urge incontinence,
usually with frequency and nocturiaUrgency: sudden compelling desire to pass urine
for fear of leakage which is difficult to deferPBS: suprapubic pain related to bladder filling
accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven uti or other obvious pathology
Abrams et.al.: Neurourology & Urodynamics, 21:167, 2002
The PBS problem (sensitivity)PBS definition has 64% sensitivity according
to Warren The restriction to “suprapubic pain” in the ICS
definition and the relationship of pain to filling were the criteria most responsible for the poor sensitivity.
Warren; Urology, 67:1138-1143, 2006
6
Incidence similar to gen populationPaul Abrams
TIME (INCREASING BLADDER VOLUME)
SENSATION
Painful Bladder Syndrome / IC
sens
atio
n
time
OAB: urgency forces voiding because of fear of leakage
ESSIC Proposed Definition
Bladder Pain Syndrome/ICBladder Pain Syndrome/IC: Chronic pelvic pain, pressure, or discomfort
perceived to be related to the urinary bladder accompanied by at least one other urinary symptom like persistent urge to void or urinary frequency. Confusable diseases as the cause of the symptoms must be excluded.
Epidemiology Studies Left to Devise Their Own Definitions
Results Vary Widely Depending Upon Definition and Methodology
0
2
4
6
8
10
12
14
16
18
20
Japan Holland USA Finland
ItoBadeRobertsOravisto
Prevalence per 100,000Female population
Initial Studies Were Based on Physician Assigned Diagnosis
Ann Chir Gynaecol Fenn64:75, 1975
Roberts: BJU International 91:181, 2003
Bade: J. Urol154:2035, 1995
Ito: BJU International86:634, 2000
7
Methodologies
Held: “IC Dx” urologist survey and general population survey: 34.4/100,000 (USA)Curhan: Nurses Health Study; self report and record review: 60/100,000 (USA) Clemens: Portland managed care: assigned Diagnosis without exclusion criteria: 158/100,000 (USA)
Held, Hanno, Wein, et.al.: in Hanno: Interstitial Cystitis, Springer Verlag, London 1990
Curhan: J. Urol,161:549, 1999Clemens: J.Urol 173:98, 2005
0
20
40
60
80
100
120
140
160
Japan Holland USA Finland
ItoBadeRobertsOravistoHeldCurhanClemens
Prevalence per 100,000Female population
Methodologies
Jones and Nyberg: Self report, National Household Interview Survey: 450/100,000Hong-Jeng Yu: O’Leary Sant scores: 310/100,000 (Tapei)Leppilahti: O’Leary Sant Scores + exam: 300/100000 (Finland)Temml: O’Leary Sant Scores: 306/100000 (Austria) Hong-Jeng Yu: Pan Asian
Interstitial Cystitis Meeting,Tapei, April 2006
Jones and Nyberg: Urology49S:2, 1997
Leppilahti: J. Urol, 174:581, 2005
TemmL: European Urol.(2006) 08.028
0
50
100
150
200
250
300
350
400
450
Japan Holland USA Finland Taiwan Austria
ItoBadeRobertsOravistoHeldCurhanClemensJonesYuLeppilahatiTemml
Prevalence per 100,000Female population
8
IC/PBS: CLINICAL HISTORY
PELVIC PAINTypical Suprapubic “Pressure” sensationPain in lower abdomen, low back, inguinal area, vagina, urethra, scrotum or testes, multiple locationsPain with/after intercourse in vagina, penile shaft – can last for daysDysuria55% with constant pain – severity is highly variablePain characterized as spasms, hot stabbing, worse in upright position, worse with emotional stress
IC/PBS: CLINICAL HISTORY
FREQUENCY/URGENCYMay be Presenting Symptom (No Pain)Often develops gradually – Not noticed immediatelyDaytime Frequency: 8-50 Voids/DayNocturia – Variable
IC/PBS: PHYSICAL EXAMINATION
Abdominal, Pelvic and Neurological exam findings – nonspecificSuprapubic tenderness to deep palpation on bimanual examBladder base and urethra tender in femalesSpasticity of levator musclesMales with normal genitalia and DREExam must R/O: Active Vaginitis, Urethral diverticulum, Vulvadynia, Prostate cancer, major Prolapse (May co-exist with IC/PBS)
IC/PBS: DIFFERENTIAL DIAGNOSIS
UROLOGICALOveractive BladderBacterial CystitisChronic Abacterial Prostatitis/CPPSCIS Bladder/CarcinomaUrethritisUrethral Diverticulum (Symptomatic)Ureteral or Bladder CalculusRadiation Cystitis
IC/PBS: DIFFERENTIAL DIAGNOSIS
GYNECOLOGICAL DISORDERSEndometriosisPelvic Inflammatory DiseaseVulvadyniaVulvar VestibulitisVaginitisUrogenital AtrophyActive Herpes InfectionPelvic Malignancy/Large FibroidMajor Pelvic Prolapse
9
IC/PBS: DIFFERENTIAL DIAGNOSIS
GASTROENTEROLOGY
Irritable Bowel SyndromeInflammatory Bowel DiseaseGI Pelvic MalignancyColovesical FistulaDiverticular diseaseHernia
IC/PBS: ASSOCIATED DISORDERS
Strong Medication Sensitivity or Allergic ReactionsFood AllergiesSinusitisHay FeverIBSSpastic colonArthritisFrequent URIs
All p values <0.001 compared to controls (Koziol JA. Urol Clin North Am. 1994)
IC/PBS: “When Do I Suspect It?”
Triad of Pain, Frequency and UrgencyAND
Physical exam excludes Vaginitis, Urethral or Vulvar lesion or Infection
ANDUA is negative for Hematuria
ANDUrine culture during symptoms is Negative
ANDNo Hx of Neurological problem, Pelvic trauma,
Malignancy or recent Pelvic Surgery
Diagnosis: cystoscopy
Cystoscopic findings (Hunner’s ulcer-vulnus, glomerulations) are not well described and classifiedBoth can be present in patients without PBS/IC and absent in patients with the symptom complexResearch into treatment results and prognosis as related to cystoscopic findings is needed
IC/PBS: HYDRODISTENTIONMETHOD
Should be done under Anesthesia to allow sufficient distentionIrrigant should be 80-100 cm above bladder to avoid ruptureDistention held at capacity for 1-2 mins, then drained
POSITIVE FINDINGSGlomerulationsHunners ulcerFissures and Fibrosis that Bleeds
Important to R/O – CIS, Papillary Bladder Cancer
Glomerulations of I.C.
The diagnosis of PBS/IC is clinical and based on symptomatology and exclusion. There is no evidence to qualify or quantify the symptoms to include or exclude patients from the diagnosis of IC/PBS
10
IC/PBS: Cystscopic Evaluation
Carcinoma in situ Hunners Ulcer
IC Patients vs Normal Subjects
Volume (mL)Avg Normal =1,115 mL; Avg IC = 575 mL
Nu
mbe
r of
Peo
ple
0
10
20
30
40
50
60
70
80
100 200 300 400 500 600 700 800 1400+1300900 1000 1100 1200
Normal SubjectsIC Patients
Parsons CL. Interstitial cystitis. Urogynecology and Urodynamics; Theory and Practice. 1996;409-425.
Anesthetic Bladder Capacity
PROBLEMSGlomerulations not specific for IC – seen in most inflammationsGlomerulations seen in underfilled bladder after prolonged distentionGlomerulations absent in up to 20% of patients with Classic SymptomsNo correlation between degree of glomerulations and symptomsOnly Hunners ulcers – Diagnostic for IC
IC/PBS: HYDRODISTENTION
Diagnosis: Urodynamics
No data support or refute useStudies needed to determine significance of urodynamic detrusor overactivity that is found in14% of these patientsStudies needed to find prevalence of BOO in males with PBS/IC symptoms, and influence of treatment
IC/PBS: URODYNAMIC EVALUATION
Findings Nonspecific for ICUDS shows “Sensory Urgency” with low First Sensation of Filling and CapacityFilling usually stable but can have Phasic contractions (19%)Compliance is Normal except in fibrotic bladdersUrethral tenderness from catheter limits interpretation of Pressure/Flow study – Need to R/O anatomical obstruction in men
IC/PBS: O’LEARY-SANT QUESTIONNAIRE
Self administered validated questionnaireSx index correlates with impact on daily living activitiesProblems index documents Sx botherBoth indices strongly discriminate IC patients from controlsNot designed as a screening questionnaire to diagnose IC
11
IC/PBS: GYN/URO DIAGNOSIS
ENDOMETRIOSISDiverse symptoms include –dysmenorrhea, dyspareunia, dyscheziaURO involvement include – frequency, dysuria and hematuriaDiagnostic Laparoscopy – Gold standard with “Powder Burn” lesionsCombined procedure with cystoscopy, hydrodistention for complicated patient history
Endometriosis – Laparoscopic Appearance
Chocolate cyst of the ovary
Powder burn lesions of the uterosacral ligaments
Management of PBS/IC
Primary Treatment GoalsReduce SymptomsImprove Quality of Life
Complex etiologies often require multimodality therapy
Early treatment may prevent disease progression (not proven)
Management of PBS/IC
Treatment Options for PBS/IC
Behavioral/Diet ModificationOral Pharmacologic TherapyIntravesical TherapyPelvic Floor Physical TherapySurgical Therapy
Management of PBS/IC
Behavioral Therapy for PBS/IC
Diet Avoidance TherapyAcidic fruits, spicy foods, processed meats, caffeine, alcohol, preservatives.
Bladder RetrainingRelaxation TechniquesCoping Strategies
12
Management of PBS/IC
Pharmacologic Therapy
Antidepressants (Amitriptyline)Anticonvulsants (Gabapentin,Pregabalin)Antihistamines (Hydroxyzine)Immunosuppressants (Cyclosporin,Cellcept)Analgesics/NarcoticsGAG Layer Replacement (PPS)
Management of PBS.ICIntravesical Agents
BCG: failed NIDDK RCTDMSO/Heparin/SolumedrolHyaluronan: failed 2 large US RCTIntravesical Elmiron: 2 small positive trials*RTX: failed US phase 2 trial; recent trials inconclusive**Alkalanized lidocaine solutions
*Bade, J Urol, 163S:60, 2000Davis, J Urol, 179:177-185, 2008
**Urol Int 2007;78(1):78-81Hinyokika Kiyo 2006; 52(12):911-3J. Urol, 173:1590, 2005
Intradetrusor: Botulinum A Toxin
One year follow-up of open label study in BPS/IC n=15 (200u in 20cc, trigone, lateral walls)At 3 months, 86% had pain reliefAt 5 months 26% had pain reliefAt 12 months pain recurred in all patients9 patients had dysuria post treatment persisting 1-5 months3 pts needed CIC after Rx, 2 at 3 mos and 1 at 5 mos
Giannantoni et al: J Urol, 179:1031, 2008
Management of PBS/IC
Pelvic Floor Physical Therapy
Reports of symptom reduction using myofascialtrigger point release therapy using nonstandardized techniques and no controls.
NIDDK/NIH protocol ongoing thru the ICCRN network to standardize technique and include sham control.
Sacral nerve neuromodulation
Sacral Nerve Modulation is a promising surgical treatment for IC/PBS however remains still investigationalLevel 2 evidenceGrade D recommendation
Sacral Neuromodulation
Urgency frequency long term Urgency frequency long term followupfollowupElhilaliElhilali: N=22; 45% persistent improvement : N=22; 45% persistent improvement after successful test stimulation 5after successful test stimulation 5--17 year 17 year f/uf/u2 2 icic patients no improvementpatients no improvementComiter had 17 of 25 success in IC at 14 months in those permanently implanted
Urol 65:1114, 2005J. Urol 169:1369, 2003
13
•Bladder augmentationCystoplastyCystoplasty with supratrigonal resection Cystoplasty with subtrigonal cystectomy
No outcome difference among bowels segments except for dysuria associated with gastric tissue substitution.Weak evidence that cystoplasty with supratrigonalresection is superior.Subtrigonal cystectomy with cystoplasty has no outcome advantage over supratrigonal cystectomy but is associated with more complications.Literature suggest: 1. using detubularized intestinal segment, 2. performing supratrigonal bladder resection 3. selecting patients with low cystoscopic bladder capacity
Level 4 evidenceGrade C recommendation
Total cystectomy and urethrectomy
Urinary diversion with or without cystectomy and orthotopic continent bladder may be the ultimate option for refractory patients. Continent diversion may have better cosmetic and life style outcome but recurrence of IC in the pouch is a real possibility. There is no literature evidence of any advantage of continent surgery
Level of evidence: 4Grade of recommendation: C
You’ve got to ask yourself the question, “Do you feel lucky?”
Time for a cystectomy?
SURGERY FOR PBS / IC
Surgical options should be considered only when all conservative treatment failed. The patient should be informed of all aspects of surgery and understand consequences and potential side effects of surgical intervention.
IC/PBS: ALGORITHM
EducationDiet modification
Analgesics
Treatment
History/PhysicalUA, Culture,
CytologySx questionnaire
Suspect PBS
Appropriate work-up
Hematuria,Infection, + Cytology,
+ PE finding
PBS
Typical Hx
GYN referralUDS
Imaging studiesGI work-up
Atypic
al Hx
Elavil
Inadequate response
Follow & Support
Improved
Improved
Hydrodistention +/- Laparoscopy
Failed
Failed
Endometriosis,BOO,
Calculi, etc.
Oral agents (PPS)Intravesical Tx
Pelvic floor rehabInadequate response
Oral agentsIntravesical Tx
Pelvic floor rehab
Research ProtocolsNeuromodulation
Pain Clinic
Follow& Support
ConsiderCystectomy
Inadequate response
Improved
Failed
IC/PBS: ALGORITHM
14
IC, PBS/IC, BPS/IC, BPS
What’s now??What’s Next???
Active Efforts Are UnderwayDefinitionNomenclatureClassification
ESSIC
Pan Asian IC AssociationIASP and PUGO
ICICJ
NIDDK
ICA
New Classification and Nomenclature
IASP: International Association for the Study of PainProposal from PUGO: Pain of Urogenital OriginScheduled to be presented August 2008 at Glasgow Meeting of IASP
Description is broad: High sensitivityLow specificity
Increasing specificity
High sensitivityHigh specificity
Broad description of symptoms that warrant further investigation
to detect bladder disease
Diagnosis or exclusion of a confusable disease as
the cause of the bladder-related
symptoms
Confirmation and typing
of PBS
PUGO/IASP TAXONOMY
Axis 1: RegionAxis 2: SymptomAxis 3: End Organ (history, examination, investigation)Axis 4: Referral CharacteristicsAxis 5: Temporal CharacteristicsAxis 6: CharacterAxis 7: Associated SymptomsAxis 8: Psychological Symptoms
Chronic pelvic pain
Pelvic pain syndrome
Urological
Bladder pain syndrome
Interstitial cystitis
15
PBS becomes BPS, or does it?Bladder pain syndromeUrethral pain syndromeProstate pain syndrome (formerly CPPS type 3) (formerly nonbacterial prostatitis)Scrotal pain syndrome
Testicular, epididymal, vasal pain syndromes
Penile pain syndrome
ESSIC Classification of BPS
Nordling J and van de Merwe JP. ESSIC web site, Accessed September 2006.
3C2C1CXCPositive
3B2B1BXBInconclusive
3A2A1AXANormal
3X2X1XXX Not Done
HunnerLesion
Glomerulations
NormalNot Done
BIOPSY
CYSTOSCOPY WITH HYDRODISTENTION
PBS
PBS
PBS
IC
PBS
PBS
PBS
IC
IC IC
IC
IC
IC
IC
IC
IC
IC/PBS: RX ResearchICCRN Trials: results later this year
Trial 1Amitriptyline plus behavioral modification vs behavioral modification alone in newly diagnosed PBS patients
Trial 2Cellcept® vs placebo in refractory IC patients12-week treatment, then 12-week follow up
Trial 3Pelvic floor physical therapy vs placebo
Oxford Evidence Based Analysis2008: what works
3 therapies supported by high level of evidence in the literature
Amitriptyline, DMSO, CimetidineEAU-EBU Update Series 4(2006) 47-61
Everything else is really “expert” opinionCyclosporine clinical trials are extremely interesting; ? After rebound after Rx?
J. Urol. 1996, 155:159-163J. Urol. 2004, 171: 2138-2141J. Urol. 2005, 174: 2235-2238
General Considerations
• Treatments are empiric as cause is unknown• Symptoms can be controlled with one or
variety of treatments in majority of patients• Little evidence that treatment does more
than influence symptomatic expression of IC
• 50% incidence of remission (8 month duration) unrelated to specific treatment
More Cautions
• Patients can be victims of unorthodox providers, untested therapies, unproven surgical procedures
• Few treatments have been subjected to placebo-controlled trial
• Need for skepticism
16
Assessing Treatment Results
• Placebo effect + natural history + regression to the mean = high rates of good outcomes
• Caution: statistical versus clinical significance
• “A difference to be a difference must make a difference” Gertrude Stein
Current Pathways
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Bladder Pain Syndrome/Interstitial Cystitis
Old Paradigm IC:Identify Marker
Determine PathophysiologyModify Pathophysiology
New Paradigm:Bladder Pain Syndrome/IC
Treat the PainLocal Causes in BladderPrevent Centralization
New NIH ApproachUrologic Chronic Pelvic Pain
• Abandon “hit-or-miss” approach to selection of candidate therapies for clinical trials
• Integrate both basic and clinical research• Knowledge about “disease mechanisms”
used to identify targets for suitable agents to be tested in future clinical trials
A Multi-disciplinary Approach to the Study of Chronic Pelvic Pain
Syndromes: The MAPP Research Network
To appear summer 2008
Primary Objectives of the MAPP-I
• Conduct basic and clinical research studies of IC/PBS and CP/CPPS considering these syndromes as systemic disorders (cross-studies of chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, migraine headacheand vulvodynia)
• Can co-morbid illnesses in patients with IC/PBS or CP/CPPS provide additional insights into these syndromes?
External AdvisoryCommitteeNIDDK
Data and Administrative
Core
MAPP Research Network Discovery
SitePhenotype
Basic
Basic
Epi
Epi
Discovery Site
Phenotype
Basic
Phenotype
Epi
Discovery Site
Phenotype
Basic
Epi
Discovery Site
Phenotype
Basic
Epi
Epi
Epi
Discovery Site
Phenotype
Basic
Epi
Discovery Site
Phenotype
Basic
Basic
Epi
Phenotype
Tissue & Technology
Core
Trans-NIH Pain Advisory Group
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Interstitial Cystitis / Painful Bladder Syndrome / Bladder Pain Syndrome: The Evolution of a New Paradigm Evolution of a Definition
`When I use a word,' Humpty Dumpty said, in rather a scornful tone, `it means just what I choose it to mean -- neither more nor less.'
`The question is,' said Alice, `whether you can make words mean so many different things.'
`The question is,' said Humpty Dumpty, `which is to be master -- that's all.' 1
Figure 1
Tage Hald revered to it as “a hole in the air”.2 It’s been 20 years since the NIDDK proposed diagnostic criteria for entrance into research studies of interstitial cystitis.3, 4, and so inadvertently defined the disorder for a generation of urologists. There has been a change in the way the disease (symptom complex, syndrome?) is perceived, and it is valuable to review briefly some of the ways it has been defined in the past.
1887 Skene: an inflammation that has destroyed the mucous membrane partly or wholly and extended to the muscular parietes5 1917 Hunner: a peculiar form of bladder ulceration whose diagnosis depends ultimately on its resistance to all ordinary forms of treatment in patients with frequency and bladder symptoms (spasms)6 1951 Bourke: …patients who suffer chronically from their bladder; and we mean the ones who are distressed, not only periodically but constantly, having to urinate at all moments of the day and of the night suffering pains every time they void7
1978 Messing & Stamey: Nonspecific and highly subjective symptoms of around the clock frequency, urgency, and pain somewhat relieved by voiding when associated with glomerulations upon bladder distention under anesthesia8 1990 Revised NIDDK Criteria: Pain associated with the bladder or urinary urgency, and, glomerulations or Hunner’s ulcer on cystoscopy under anesthesia in patients with 9 months or more of symptoms, at least 8 voids per day, 1 void per night, and cystometric bladder capacity less than 350cc4 1997 NIDDK Interstitial Cystitis Database Entry Criteria: Unexplained urgency or frequency (7 or more voids per day), OR pelvic pain of at least 6 months duration in the absence of other definable etiologies9 When a comparison of the NIDDK revised criteria with the database entry criteria
was performed, it was apparent that up to 60% of patients clinically believed to have interstitial cystitis by experienced clinicians were being missed when the NIDDK research criteria were used as a definition of the disease.10
The lack of clarity in terms of definition is highlighted when we look at the results of numerous epidemiology prevalence studies that show widely disparate results depending upon how one defines the disorder.11-16 (figure 2) These studies show prevalence rates in 100,000 females from 1.8 when physician assigned diagnoses were used in Olmstead County, Minnesota17 to 450 when patients self-reported a diagnosis in the National Household Interview Survey.18 Interestingly, rates are surprisingly similar in Finland, Taiwan, and Austria at about 300 per 100,000 females when a high O’Leary-Sant symptom score is used as a surrogate for a diagnosis of interstitial cystitis.19-22
Figure 2
Unfortunately, histopathology does not really help when it comes to defining this symptom complex. One can have bladder biopsies consistent with the diagnosis of IC, but there is no microscopic picture pathognomonic of this disorder. The role of histopathology in the diagnosis of IC is primarily one of excluding other possible diagnoses. Rosamilia and colleagues reviewed the pathology literature pertaining to interstitial cystitis and presented their own data.23, 24 They compared forceps biopsies from 35 control and 34 IC patients, 6 with bladder capacities less than 400cc under anesthesia. Epithelial denudation, submucosal edema, congestion and ectasia, and inflammatory infiltrate were increased in the IC group. Submucosal hemorrhage did not differentiate the groups, but denuded epithelium was unique to the IC group and more common in those with severe disease. The most remarkable finding in this study was that histologic parameters were normal and indistinguishable from control subjects in 55% of IC patients. Method of biopsy can be important in interpreting findings, because transurethral resection biopsies tend to show mucosal ruptures, submucosal hemorrhage, and mild inflammation25 while histology is normal approximately half the time with cold-cup forceps biopsies.26, 27 Susan Keay’s finding that cells from the bladder lining of normal controls grow significantly more rapidly in culture than cells from IC patients, and her subsequent discovery and description of a frizzled 8 protein produced by bladder uroepithelial cells of IC patients, “antiproliferative factor (APF)”, holds promise as a marker of the disease,
and perhaps a way to define it. As of 2007, neither have her findings been replicated by other centers, nor has a commercially available assay for APF been approved. The use of APF as a diagnostic marker and a part of the clinical definition of the syndrome remains tantalizing but not clinically accessible.28 Is there a clinical test that by virtue of its sensitivity and specificity could be used to diagnose IC and thereby become a part of the definition of the disorder? Unfortunately, there is not. The potassium chloride test proposed by Parsons29, an intravesical challenge comparing the sensory nerve provocative ability of saline versus potassium chloride using a 0.4M KCl solution, has not gained acceptance as a diagnostic test for a variety of reasons.30 It has neither the specificity nor the sensitivity to be used as a diagnostic test, and therefore results of the test could not be a part of any clinically useful definition.
The twenty-first century begins with much confusion as to how to define this 100 year-old syndrome, and the need for a clinically useful, universally accepted way to characterize IC has become a high priority. Abrams and the International Continence Society (ICS) preferred Bourke’s term “painful bladder” and defined painful bladder syndrome as “the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven urinary infection or other obvious pathology”. Rather than drop the designation of IC all together, they limited it to patients with painful bladder who had “typical cystoscopic and histological features” without identifying those features.31 The term “urgency” was effectively taken out of the IC equation, and used to identify “the complaint of a sudden compelling desire to pass urine which is difficult to defer”. It became an integral part of the definition of overactive bladder: urgency with or without urge incontinence, usually with frequency and nocturia. Some degree of confusion has resulted32 and patient organizations have not been happy to give up the “urgency” term, one that many patients identify with their IC symptoms.33 When looking at the Interstitial Cystitis Symptom Index (O’Leary-Sant ICSI), the ICSI question for urgency “the strong need to urinate with little or no warning”, consistently yields lower scores than the severity question of “the compelling urge to urinate that is difficult to postpone”.34 Warren compared the ICS painful bladder criteria with symptoms of patients he recruited for a case control study of newly diagnosed women with interstitial cystitis.35 His criteria for entrance into the study included women greater than 18 years of age with symptom onset within 12 months. They had greater than 4 weeks of perceived bladder pain > 3 on a 10 point Likert scale and at least two of frequency (>8/24 hours), urgency (>3 on a Likert scale), or nocturia. Exclusionary criteria were those of the NIDDK. He found that the ICS definition identified only 66% of his 138 cases. Those who met the definition did not differ from those who did not. The restriction to “suprapubic pain” in the ICS definition and the relationship of pain to filling were the criteria most responsible for the poor sensitivity.
Soon after the ICS terminology publication, several high-profile international meetings were held to tackle the problem of definition and nomenclature, and establish a new framework for future collaborative research. While each meeting had
long, complex agendas, it is useful to look at how each approached the definition of the syndrome.
The first of these was the International Consultation on Interstitial Cystitis Japan (ICICJ) held in Kyoto in March 2003 under the direction of Tomohiro Ueda, Grannum Sant, Naoki Yoshimura, and this author.36 This meeting concluded by suggesting the following:
Interstitial cystitis should be suspected and further investigation is recommended in any patients with pelvic pain and urgency and/or urinary frequency associated with no obvious treatable condition/pathology. The term IC should be expanded to a term IC/CPPS (interstitial cystitis / chronic pelvic pain syndrome) when pelvic pain is at least of 3 months duration and associated with no obvious treatable condition/pathology.
The ICICJ was quickly followed by a meeting of a newly formed European Society for the study of IC (ESSIC). The first meeting was held in Denmark in May 2003, with annual meetings thereafter. A process was begun which culminated in 2005 with the acceptance by ESSIC of the ICS definition of painful bladder syndrome with only minor modification.37 Interstitial cystitis was a subset of painful bladder syndrome defined as: …a disease of unknown origin consisting of the complaint of suprapubic pain related to bladder filling accompanied by other symptoms, such as increased daytime (>8x) and nighttime (>1x) frequency, and with cystoscopic (glomerulations and/or Hunner’s lesions) and/or histological features (mononuclear inflammatory cells including mast cell infiltration and granulation tissue) in the absence of infection or other pathology. On October 29th 2003 the NIDDK convened a meeting of the members of the Interstitial Cystitis Epidemiology Task Force, the IC executive committee, ad hoc participants, and National Institutes of Health staff to review the status of current investigations of IC and to plan new epidemiology investigations.38 The following served as their working definition: Interstitial cystitis is a symptomatic diagnosis based on the presence of three key symptoms: pain, urgency, and frequency, as well as exclusion of a short list of other conditions that cause the same symptoms. Pain is the most consistent and disabling symptom for IC patients. Some will not use the term pain, but will rather describe a sense of pressure or discomfort. Typically, but not always, the pain is worse with filling of the bladder and is relieved by emptying of the bladder. Urgency in IC patients differs from that experienced by patients with urinary incontinence. In IC patients, the urgency is driven by pain, in patients with incontinence (detrusor overactivity), it is driven by their fear of losing control. Not enough information is available on normal variability of urinary frequency to establish a number that can help diagnose IC. Immediately following the epidemiology meeting, the NIDDK in conjunction with the Interstitial Cystitis Association held a basic and clinical science symposium.39 It concluded: The struggle to define IC will continue. Bladder pain will continue to be the key to the definition in the near future. In June 2004 the third International Consultation on Incontinence, co-sponsored by the International Consultation on Urological Diseases in official relationship with the
World Health Organization, the International Society of Urology, the International Continence Society, and the major international associations of Urology and Gynecology adopted the ICS definition of IC and PBS. It noted that because of the ambiguity in defining IC as a subset of PBS, the terms would be used together to refer to the same constellation of symptoms (PBS/IC).23 Further, it concluded that: Interstitial cystitis is a clinical diagnosis primarily based on symptoms of urgency/frequency and pain in the bladder and or pelvis. The combined term PBS/IC will be used until more specific criteria can be established. Soon after the International Consultation on Incontinence, the Multinational Interstitial Cystitis Association met to carry the discussion forward.39 The group kept the ICS definition of painful bladder syndrome, but broadened the symptom of pain to include “pressure” and “discomfort”. The group went on to note: Interstitial cystitis may be a subgroup of this larger syndrome (PBS)…but as this remains somewhat vague, a general nomenclature is preferred and the question of what is “IC” alone is left to be determined. Urgency is a common complaint of this group of patients. The ICS definition of urgency could be interpreted as compatible with either detrusor overactivity of PBS/IC. Because the term of urgency would tend to obfuscate the borders of these two conditions and may be unnecessary as a part of the definition of PBS/IC, its place in the definition will need to be worked out in conjunction with the ICS terminology committee. ESSIC presented a comprehensive report at the NIDDK 2006 “Frontiers in Painful Bladder Syndrome and Interstitial Cystitis” meeting in October 2006. A decision was made public there by ESSIC to drop the moniker “interstitial cystitis” in favor of “bladder pain syndrome”, which was to be further categorized by results of optional investigations (see below). In reaction to this, the Interstitial Cystitis Association in conjunction with the Association of Reproductive Health Professionals held a meeting in Washington in February 2007 with a cross section of invited American urologists, gynecologists, nurses, and representatives from the German patient organization and a urologist from Germany. The following definition was promulgated at the meeting and is available in the context of the proceedings at http://www.arhp.org/healthcareproviders/visitingfacultyprograms/icpbs/whitepaper.cfm IC/PBS is defined by pelvic pain, pressure, or discomfort related to the bladder, typically associated with persistent urge to void or urinary frequency, in the absence of infection or other pathology. The “persistent urge” term was meant to include the idea of urgency in the definition while not directly impinging on the ICS use of the term as defined for overactive bladder. In a compromise presented at the second International Consultation on Interstitial Cystitis Japan in March 2007, ESSIC agreed to modify the name and definition to be acceptable to all stakeholders. This was confirmed at their meeting in Muenster in May 2007. Bladder pain syndrome/interstitial cystitis 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 symptoms like persistent urge to void or urinary frequency. Confusable diseases as the cause of the symptoms must be excluded.
Further documentation and classification of BPB/IC might be performed according to findings at cystoscopy with hydrodistention and morphological findings in bladder biopsies. Evolution of Nomenclature Closely related to the issue of definition is nomenclature. In many ways nomenclature, even more than definition, has developed into to a very “hot-button” issue, and in mid 2007 there is no agreement as to how this complex syndrome should best be referred to. Changes in nomenclature have punctuated the literature over the last 170 years. The syndrome has variously been referred to as: tic doloureux of the bladder, interstitial cystitis, cystitis parenchymatosa, Hunner’s ulcer, panmural ulcerative cystitis, urethral syndrome, and painful bladder syndrome.5, 7, 40-44 The name “interstitial cystitis”, for which Skene is given credit and which Hunner popularized, is somewhat of a misnomer as in many cases not only is there no interstitial inflammation, but histopathologically there may be no inflammation at all.24, 26, 45, 46 With the formal definition of the term “painful bladder syndrome” by the International Continence Society in 200231, the terminology discussion began to take on an importance and priority not seen for decades. Perhaps the lack of progress in identifying causes of the disorder and effective treatments might somehow be related to an improper focus solely on bladder pathology, partly as a result of the potentially misleading name of the disorder. Was the perspective of researchers and clinicians somehow off-target, and should this disorder be looked at as part of a new paradigm (perhaps through a pain paradigm)? In Kyoto at the ICICJ in March 2003 it was agreed that the term “interstitial cystitis” should be expanded to “interstitial cystitis/chronic pelvic pain syndrome” when pelvic pain is at least of 3 months duration and associated with no obvious treatable condition/pathology.36 The European Society for the Study of Interstitial Cystitis held its first meeting in Copenhagen soon after Kyoto. Nomenclature was discussed, but no decision was reached, as the meeting concentrated on how to evaluate patients for diagnosis.47 At the meeting of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2003 entitled “Research Insights into Interstitial Cystitis” it was concluded that “interstitial cystitis” will inexorably be replaced as a sole name for this syndrome. It will be a gradual process over several years. At the meeting it was referred to as “interstitial cystitis/painful bladder syndrome” in keeping with International Continence Society nomenclature.39 At the meeting of the Multinational Interstitial Cystitis Association in Rome in 2004, it was concluded that the syndrome should be referred to as “Painful Bladder Syndrome / Interstitial Cystitis” or “PBS/IC”.39 That same year the International Consultation on Incontinence included the syndrome as a part of the Consultation. Interestingly, the chapter in the report was titled “Painful Bladder Syndrome (including interstitial cystitis), suggesting that IC formed an identifiable subset within the broader syndrome. Because such a distinction is difficult to define, within the body of the chapter, co-authored by 9 committee members and 5 consultants from 4 continents, it was referred to as PBS/IC (one inclusive entity).23 In June 2006 Abrams and colleagues published an editorial that attacked the nomenclature problem head-on.48 They noted that “It is an advantage if the medical term
has clear diagnostic features that translate to a known pathophysiological process so that effective treatment may be given. Unfortunately, the latter is not the case for many of the pain syndromes suffered by patients seen at most pain, gynecological, and urological clinics. For the most part these ‘diagnoses’ describe syndromes that do not have recognized standard definitions, yet infer knowledge of a pathophysiologic cause for the symptoms. Unfortunately the terminology used to describe the condition may promote erroneous thinking about treatment on the part of physicians, surgeons and patients. These organ based diagnoses are mysterious, misleading and unhelpful, and can lead to therapies that are misguided or even dangerous”. The editorial went on to note that a single pathological descriptive term (interstitial cystitis) for a spectrum of symptom combinations ill serves patients. The umbrella term “painful bladder syndrome” was proposed, with a goal to define and investigate subsets of patients who could be clearly identified within the spectrum of PBS. It would fall within the rubric of chronic pelvic pain syndrome. Sufferers would be identified according to the primary organ that appears to be affected on clinical grounds. Pain not associated with an individual organ would be described in terms of the symptoms. One can see in this the beginnings of a new paradigm that might be expected to change the emphasis of both clinical and basic science research, and which removes the automatic presumption that the end-organ in the name of the disease should necessarily be the sole or primary target of such research. At the major biannual interstitial cystitis research conference in the fall of 2006 held by the National Institute of Diabetes and Digestive and Kidney Disease (Frontiers in Painful Bladder Syndrome and Interstitial Cystitis), the ESSIC group was given a block of time with which to present their thoughts and conclusions.49 Because PBS did not fit into the taxonomy of other pelvic pain syndromes such as urethral or vulvar pain syndromes, and because IC is open to different interpretations, ESSIC decided to rename PBS as Bladder Pain Syndrome (BPS) followed by a type designation. BPS is indicated by two symbols, the first of which corresponds to cystoscopy with hydrodistention findings (1,2,or 3 indicating increasing grade of severity) and the second to biopsy (A,B, and C indicating increasing grade of severity of biopsy findings). While neither cystoscopy with hydrodistention nor bladder biopsy were prescribed as an essential part of the evaluation, by categorizing patients as to whether either procedure was done, and if so the results, it becomes possible to follow patients with similar findings and study each identified cohort to compare natural history, prognosis, and response to therapy. Figure 3 shows the layout of this type of classification. Boxes with a 2, 3, or C designation might have been diagnosed as “interstitial cystitis” by past criteria, and the rest would fall within the broader “painful bladder syndrome” designation. Both terms become superfluous for purposes of categorization if one adopts the ESSIC classification of BPS with the appropriate letter and number. As Baronowski conceives it, BPS is thus defined as pain with a collection of symptoms, the most important of which is pain perceived to be in the bladder. IC is distinguished as an end organ, visceral-neural pain syndrome, while BPS can be considered a pain syndrome that involves the end organ (bladder) and neuro-visceral (myopathic) mechanisms. In IC, one expects end organ primary pathology. This is not necessarily the case in the broader BPS. Figure 3
ESSIC Classification of BPS
ESSIC web site, Nordling, J and van de Merwe, JP, September 2006
3C2C1CXCPOSITIVE
3B2B1BXBINCONCLUSIVE
3A2A1AXANORMAL
3X2X1XXXNOT DONE
HUNNER’SLESION
GLOMERULATIONS
NORMALNOT DONE
BIOPSY
CYSTOSCOPY WITH HYDRODISTENTION
Another way to conceptualize this, suggested by Baranowski, is with the following diagram. Figure 4
description is broad: high sensitivitylow specificity
increasing specificity
high sensitivityhigh specificity
broad description of the symptoms that warrant further investigations
to detect bladder disease
diagnosis or exclusion of a confusable disease as
the cause of the bladder-related
symptoms
confirmation and typing
of PBS
The target diagram conceptualizes this from the viewpoint of interstitial cystitis. Figure 5
Chronic pelvic pain
Pelvic pain syndrome
Urological
Bladder pain syndrome
Interstitial cystitis
There may be many causes of chronic pelvic pain. When an etiology cannot be
determined, it is characterized as pelvic pain syndrome. To the extent that it can be distinguished as urologic, gynecologic, dermatologic, etc., it is further categorized by organ system. A urologic pain syndrome can sometimes be further differentiated on the site of perceived pain. Bladder, prostate, testicular, epididymal pain syndromes follow. Finally, types of bladder pain syndrome can be further defined as interstitial cystitis, or simply categorized by ESSIC criteria. This new perspective, which remains in its formative stages, will likely be presented in a more crystallized form by Andrew Baranowski as a part of the International Association for the Study of Pain conference in Glasgow in 2008.
Patient groups have expressed significant reservations with regard to any nomenclature change that potentially drops the “interstitial cystitis” moniker. The meeting organized by the Association of Reproductive Health Professionals and the Interstitial Cystitis Association concluded that “The nomenclature of IC/PBS may need to change, but change should not be undertaken now because there is insufficient evidence to support a change. Any change in nomenclature should be evidence-based. This group favors retaining IC in whatever name is considered in the future and positioning it first, as in IC/PBS.”33 Their objections include the following:
1. Bladder Pain Syndrome is too broad a term 2. Name change will result in decreased recognition of the syndrome after years
of efforts to increase awareness of the name IC 3. Patients, legislators, and the general public will be adversely impacted by a
name change 4. The U.S. Social Security Administration and private insurance recognizes IC
but not the term BPS, and benefits could be adversely affected. 5. Possible negative impact on research funding 6. Negative impact on literature searches and information gathering
As a result of these concerns, ESSIC plans to append the IC term to the Bladder Pain Syndrome nomenclature for the foreseeable future, referring to the syndrome as BPS/IC.
The New Paradigm As a world wide community of health care professionals, we are reliant on use of a single medical language to communicate. Ideally, terminology should be easily recognizable throughout the global medical community. While much of the discussion may seem pedantic, it is in reality of the utmost importance and represents nothing short of a new paradigm with which to view the interstitial cystitis syndrome in a new context. This can be summarized in figure 6. Figure 6
Paradigm Change
Interstitial CystitisPainful Bladder Syndrome
IC:identify marker
Determine pathophysiologyModify pathophysiology
Bladder Pain SyndromeTreat the Pain
Treat Associated DisordersIdentify Local causes in bladder
Prevent Central Sensitization
InflammatoryBladder Disorder
ChronicPain Syndrome
Efforts to establish a consensus for a clinical definition, nomenclature, and diagnostic algorithm through the auspices of the American Urological Association and the European Association of Urology are underway. The NIDDK is planning similar meetings to bring together a definition and appropriate nomenclature for the clinical and basic research community. It is hoped that these efforts will be somehow linked to provide a conclusion satisfactory to all stakeholders, and which is consistent world-wide. Hopefully the Food and Drug Administration will find the efforts worthwhile, and signal the pharmaceutical industry how best to proceed with clinical research studies based on the paradigm so that the field can advance for the benefit of all patients.
Legends
OLD PARADIGM NEW PARADIGM
Figure 1: Humpty Dumpty (public domain) in Alice’s Adventures in Wonderland and Through the Looking Glass at www.authorama.com/through-the-looking-glass-6.html Figure 2: IC prevalence per 100,000 female populations (see text for explanation) Figure 3: Classification of Bladder Pain Syndrome by the European Society for the Study of Interstitial Cystitis (see text for explanation) Figures 4 and 5: Proposed classification system for chronic pain syndromes; where interstitial cystitis might fit in. Initial proposal by Baronowski49 Figure 6: Paradigm change for interstitial cystitis to bladder pain syndrome (see text)
Reference List
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(3) Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29, 1987. J Urol 1988 July;140(1):203-6.
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(17) Roberts RO, Bergstralh EJ, Bass SE, Lightner DJ, Lieber MM, Jacobsen SJ. Incidence of physician-diagnosed interstitial cystitis in Olmsted County: a community-based study. BJU Int 2003 February;91(3):181-5.
(18) Jones CA, Nyberg L. Prevalence of interstitial cystitis in the United States. J Urol 151, 423A. 1994. Ref Type: Abstract
(19) Yu H-J. Prevalence of Interstitial Cystitis in Taiwan. 2006 Apr; 2006.
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(21) Leppilahti M, Tammela TL, Huhtala H, Auvinen A. Prevalence of symptoms related to interstitial cystitis in women: a population based study in Finland. J Urol 2002 July;168(1):139-43.
(22) Leppilahti M, Sairanen J, Tammela TL, Aaltomaa S, Lehtoranta K, Auvinen A. Prevalence of clinically confirmed interstitial cystitis in women: a population based study in Finland. J Urol 2005 August;174(2):581-3.
(23) Hanno P, Baranowski A, Fall M et al. Painful bladder syndrome (including interstitial cystitis). In: Abrams PH, Wein AJ, Cardozo L, editors. Incontinence. 3 ed. Paris: Health Publications Limited; 2005. p. 1456-520.
(24) Rosamilia A, Igawa Y, Higashi S. Pathology of interstitial cystitis. Int J Urol 2003 October;10 Suppl:S11-S15.
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