1. Interstitial Cystitis/Painful Bladder
Syndrome: A Primer and an Update
Tuesday, May 20, 2008
1:45 - 3:15 p.m.
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.

2. Interstitial Cystitis/Painful Bladder
Syndrome: A Primer and an Update
Tuesday, May 20, 2008
1:45 - 3:15 p.m.
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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4. 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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6. 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

7. 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
Bladder Pain Syndrome/ with you to administer the government. What will you consider the
first thing to be done?”
Interstitial Cystitis The Master replied, “What is necessary is to rectify names.” “So!
Philip Hanno MD, MPH David Burks MD, indeed!” said Tsze-lu. “You are wide of the mark! Why must there
Professor of Urology Vattikuti Urology Institute, be such rectification?”
University of Pennsylvania Henry Ford Hospital, Detroit
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
Name in history Why is there a problem?
Tic doloureux of the Panmural ulcerative
bladder 1836 cystitis 1920
Interstitial cystitis 1878 Urethral syndrome 1949
Cystitis Painful bladder
parenchymatosa 1907 syndrome 1951
(Bourke), 2002 ICS
Hunner’s ulcer 1915 Bladder pain syndrome
2006 (ESSIC, PUGO)
What’s In A Name? What Seems Simple and Obvious
May Not Really Be
Bladder Pain / Frequency / Urgency
Frequency dependent upon drinking habits and
perspiration; absolute # may not be meaningful
Urgency 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
1

8. Painful Bladder Syndrome/IC does
not stand alone Well-Defined Conditions
Infective
Cystitis
Infective Infective
Urologic
Prostatitis Urethritis
NIH Type
1 and 2 Infective
Epididymo-
Orchitis
vulvodynia Poorly Characterized Entities
PBS/IC
Testicular pain syn
Scrotal Prostate Pain
Post vasectomy
Pain NIH type 3
Epididymal pain syn
Urological
Penile Urethral
Painful Bladder migraine Pain Pain
Should Fit In
Demitrack
Pharmacogenomics 2006:7:521-528
EAU Classification Poorly Categorized Entities
Chronic Pelvic Pain Syndrome Endometriosis
Assoc Pain
Poorly characterized conditions Well characterized conditions
urological neurological Other
GYN
gynecological muscular Vulvar Vaginal
Pain Syn Pain Syn
anorectal
Feb 2003, Fall, Baranowski, et.al.
2

9. Clinical Definition: The Aunt
Definition is a Problem Minnie (hard to describe but you
How do we arrive at a clinical definition? know her when you see her)
What is/are the best definition(s) to be used We have all met, at one time or another,
in epidemiologic studies patients who suffer chronically from their
What are the best methods to develop such bladder; and we mean the ones who are
definitions distressed, not only periodically but
What can we learn about PBS/IC from the constantly, having to urinate often, at all
different epidemiologic studies? moments of the day and of the night, and
suffering pains every time they void.
Bourke, 1951
The world prior
To NIDDK
“ A hole in the air” Symptoms & Endoscopic Appearance
Tage Hald
Criteria Definition
Messing 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
Endoscopic Definition NIDDK Criteria
Hunner’s definition of To define research
Interstitial Cystitis
parameters of IC so
that clinical and basic
“…a peculiar form of
bladder ulceration whose research findings
diagnosis depends would have a common
ultimately on its resistance basis for comparison
to all ordinary forms of
treatment” in patients with Not meant to be de
frequency and bladder facto definition for the
symptoms (spasms).”
clinician
Hunner, GL, Boston Medical and Surgical Journal, 172:660, 1917
3

10. Revised NIDDK Criteria Laboratory Definition:
Pain associated with the bladder or
Antiproliferative Factor
urinary urgency and glomerulations or Unique protein found only in urine of IC patients
Hunner’s ulcer on cystoscopy under Discovered by Sue Keay, U of MD
anesthesia In search for infectious etiology of IC, cell
Long list of exclusions of other disorders cultures showed differences between IC
that might give rise to symptoms bladder and control cells
Slow growth rate of IC cells led to discovery of
9 month symptom duration antiproliferative factor
8 voids per day and nocturia X 1 APF is expressed solely in the bladder
minimum epithelium of IC patients with no expression
Less than 350 cc awake bladder capacity evident in normal human bladder epithelial cells
Interstitial Cystitis (Hanno, Wein, Staskin, Krane (eds); Springer Verlag 1990)
Not ready for
OH
OH OH
NIDDK IC Database Definition for HO
OH CO2H
O
OH
prime time
O O O
AcHN O
Entry Criteria HO OH HO
Ac NH
O O
O
Broaden criteria to attempt to validate NH2
N
H N
O
H
N
O
H
N
O
H
N COOH
N N N
NIDDK criteria H
O H
O
H
O
Include all “IC-like” patients Initial studies with 200 IC patients and 300
controls demonstrated specificity and sensitivity
Unexplained urgency or frequency (7 voids
or more a day), or pelvic pain of at least 6 APF activity and altered levels of HB-EGF and
EGF previously identified in IC urine are related
months duration
APF upregulates bladder epithelial cell production
No requirement for cystoscopy or of EGF and down-regulates production of HB-EGF
endoscopic findings in vitro
Urology, 49:5A, 64-75, 1997
NIDDK IC Database Findings
424 patients with urgency or pain or frequency
Pathologic Definition
> 6 months
90
80 Criteria
Patients 70
Fulfilled
60
Agreed Mission
50
To Have IC
40
By Expert 30
Clinicians 20 Nerve hypertrophy
10 Nonulcerative IC Hunner’s ulcer Detrusor mastocytosis
0
not meeting
Criteria meeting criteria
Missed criteria Hanno, J. Urol. 1999 Excludes tissue specific diagnoses only,
Clinical
IC Patients no pathognomonic findings
4

11. Provocative Testing Definition:
Positive Potassium Test Specificity of potassium test
50-84% false positive males with CPPS
Intravesical potassium sensitivity 23% positive in unselected women in US
testing (Parsons) uses
pharmacologic .4N, not physiologic
concentrations
+ test may indicate increased
permeability and/or increased neural Parsons, J Urol 168:1054, 2002
acuity Parsons, Urol, 60:1054, 2002
Yilmaz J Urol 172:548, 2004
Obstet Gynecol, 98:127, 2001 J Urol, 168:1054, 2002
Urology, 60:573, 2002 Urology, 59:329, 2002
Sensitivity of Potassium Test ICS Definitions
Gold Standard for Defining Unequivocal IC OAB: Urgency with or without urge incontinence,
usually with frequency and nocturia
is NIDDK Criteria Urgency: sudden compelling desire to pass urine
Up to 25% of NIDDK positive patients have for fear of leakage which is difficult to defer
a negative potassium test PBS: 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
Parsons, CL: J Urol., 1862-67, 1998
Abrams et.al.: Neurourology & Urodynamics, 21:167, 2002
Specificity of Potassium Test
36% false positive in asymptomatic men The PBS problem (sensitivity)
25% false positive in OAB PBS definition has 64% sensitivity according
Up to 100% false positive in UTI and to Warren
Radiation Cystitis The restriction to “suprapubic pain” in the ICS
33% positive in Turkish ♀ textile workers definition and the relationship of pain to
filling were the criteria most responsible for
Sahinkanat Urol Int 2008;80:52–56
the poor sensitivity.
Parsons, J Urol 1862-67, 1998
Parsons, Neurourol & Urodyn 13:515, 1994
Yilmaz, J Urol, 172:548, 2004 Warren; Urology, 67:1138-1143, 2006
5

12. ESSIC Proposed Definition
Bladder Pain Syndrome/IC:
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.
Paul Abrams
Incidence similar to gen population
Epidemiology Studies Left to Devise
Painful Bladder Syndrome / IC Their Own Definitions
Results Vary Widely Depending
S
Upon Definition and Methodology
E
N
S
A
T
I
O
N
TIME (INCREASING BLADDER VOLUME)
Initial Studies Were Based on Physician Assigned Diagnosis
20
OAB: urgency forces voiding Prevalence per 100,000
because of fear of leakage 18 Female population
16
14
12
Ito
10 Bade
Roberts
8
sensation
Oravisto
6
Ann Chir Gynaecol Fenn
4 64:75, 1975
2 Roberts: BJU
0 International 91:181, 2003
Japan Holland USA Finland Bade: J. Urol
time
154:2035, 1995
Ito: BJU International
86:634, 2000
6

13. Prevalence per 100,000
450
Female population
Methodologies 400
350 Ito
Held: “IC Dx” urologist survey and general 300
Bade
Roberts
population survey: 34.4/100,000 (USA) 250
Oravisto
Held
Curhan: Nurses Health Study; self report 200
Curhan
Clemens
and record review: 60/100,000 (USA) 150 Jones
Clemens: Portland managed care: assigned 100
Yu
Leppilahati
Diagnosis without exclusion criteria: 50
Temml
158/100,000 (USA) 0
Held, Hanno, Wein, et.al.: in Hanno: Interstitial Japan Holland USA Finland Taiwan Austria
Cystitis, Springer Verlag, London 1990
Clemens: J.Urol 173:98, 2005 Curhan: J. Urol,161:549, 1999
160
Prevalence per 100,000
140 Female population
120
Ito
100
Bade
Roberts
80
Oravisto
Held
60
Curhan
40 Clemens
20
0
Japan Holland USA Finland
Methodologies
Jones and Nyberg: Self report, National
Household Interview Survey: 450/100,000
Hong-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,
Leppilahti: J. Urol, 174:581, 2005 Tapei, April 2006
Jones and Nyberg: Urology
TemmL: European Urol.(2006) 08.028
49S:2, 1997
7

14. IC/PBS: PHYSICAL EXAMINATION
Abdominal, Pelvic and Neurological exam
findings – nonspecific
Suprapubic tenderness to deep palpation on
bimanual exam
Bladder base and urethra tender in females
Spasticity of levator muscles
Males with normal genitalia and DRE
Exam must R/O: Active Vaginitis, Urethral
diverticulum, Vulvadynia, Prostate cancer, major
Prolapse (May co-exist with IC/PBS)
IC/PBS: CLINICAL HISTORY IC/PBS: DIFFERENTIAL DIAGNOSIS
PELVIC PAIN UROLOGICAL
Typical Suprapubic “Pressure” sensation
Overactive Bladder
Pain in lower abdomen, low back, inguinal area, vagina,
urethra, scrotum or testes, multiple locations Bacterial Cystitis
Pain with/after intercourse in vagina, penile shaft – can Chronic Abacterial Prostatitis/CPPS
last for days
Dysuria CIS Bladder/Carcinoma
55% with constant pain – severity is highly variable Urethritis
Pain characterized as spasms, hot stabbing, worse in
upright position, worse with emotional stress Urethral Diverticulum (Symptomatic)
Ureteral or Bladder Calculus
Radiation Cystitis
IC/PBS: CLINICAL HISTORY IC/PBS: DIFFERENTIAL DIAGNOSIS
FREQUENCY/URGENCY GYNECOLOGICAL DISORDERS
Endometriosis
May be Presenting Symptom (No Pain) Pelvic Inflammatory Disease
Often develops gradually – Not noticed Vulvadynia
immediately Vulvar Vestibulitis
Vaginitis
Daytime Frequency: 8-50 Voids/Day
Urogenital Atrophy
Nocturia – Variable Active Herpes Infection
Pelvic Malignancy/Large Fibroid
Major Pelvic Prolapse
8

15. IC/PBS: DIFFERENTIAL DIAGNOSIS Diagnosis: cystoscopy
GASTROENTEROLOGY Cystoscopic findings (Hunner’s ulcer-vulnus,
glomerulations) are not well described and
Irritable Bowel Syndrome classified
Inflammatory Bowel Disease Both can be present in patients without
PBS/IC and absent in patients with the
GI Pelvic Malignancy symptom complex
Colovesical Fistula Research into treatment results and
Diverticular disease prognosis as related to cystoscopic findings
Hernia is needed
IC/PBS: ASSOCIATED DISORDERS IC/PBS: HYDRODISTENTION
METHOD
Strong Medication Sensitivity or Allergic Should be done under Anesthesia to allow
Reactions sufficient distention
Food Allergies Irrigant should be 80-100 cm above bladder to
Sinusitis avoid rupture
Hay Fever Distention held at capacity for 1-2 mins, then
drained
IBS
POSITIVE FINDINGS
Spastic colon
Glomerulations
Arthritis Hunners ulcer
Frequent URIs Fissures and Fibrosis that Bleeds
Important to R/O – CIS, Papillary Bladder Cancer
All p values <0.001 compared to controls (Koziol JA. Urol Clin North Am. 1994)
IC/PBS: “When Do I Suspect It?” Glomerulations of I.C.
Triad of Pain, Frequency and Urgency
AND The diagnosis of PBS/IC is
Physical exam excludes Vaginitis, Urethral or clinical and based on
Vulvar lesion or Infection symptomatology and
exclusion. There is no
AND
evidence to qualify or
UA is negative for Hematuria quantify the symptoms to
AND include or exclude patients
Urine culture during symptoms is Negative from the diagnosis of
AND IC/PBS
No Hx of Neurological problem, Pelvic trauma,
Malignancy or recent Pelvic Surgery
9

16. IC/PBS: Cystscopic Evaluation
Diagnosis: Urodynamics
No data support or refute use
Studies needed to determine significance of
urodynamic detrusor overactivity that is found in14%
of these patients
Carcinoma in situ Hunners Ulcer
Studies needed to find prevalence of BOO in males
with PBS/IC symptoms, and influence of treatment
IC/PBS: URODYNAMIC EVALUATION
Anesthetic Bladder Capacity
IC Patients vs Normal Subjects Findings Nonspecific for IC
80
IC Patients UDS shows “Sensory Urgency” with low First
70 Normal Subjects
Sensation of Filling and Capacity
Number of People
60
50
Filling usually stable but can have Phasic
40 contractions (19%)
30 Compliance is Normal except in fibrotic
20
bladders
10
0
Urethral tenderness from catheter limits
100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400+
interpretation of Pressure/Flow study – Need to
Volume (mL) R/O anatomical obstruction in men
Avg Normal =1,115 mL; Avg IC = 575 mL
Parsons CL. Interstitial cystitis. Urogynecology and Urodynamics; Theory and Practice. 1996;409-425.
IC/PBS: HYDRODISTENTION IC/PBS: O’LEARY-SANT QUESTIONNAIRE
PROBLEMS
Glomerulations not specific for IC – seen in Self administered validated questionnaire
most inflammations Sx index correlates with impact on daily
Glomerulations seen in underfilled bladder living activities
after prolonged distention Problems index documents Sx bother
Glomerulations absent in up to 20% of patients
Both indices strongly discriminate IC
with Classic Symptoms
patients from controls
No correlation between degree of
Not designed as a screening questionnaire
glomerulations and symptoms
to diagnose IC
Only Hunners ulcers – Diagnostic for IC
10

17. Management of PBS/IC
Primary Treatment Goals
Reduce Symptoms
Improve Quality of Life
Complex etiologies often require
multimodality therapy
Early treatment may prevent disease
progression (not proven)
IC/PBS: GYN/URO DIAGNOSIS
Management of PBS/IC
ENDOMETRIOSIS
Diverse symptoms include – Treatment Options for PBS/IC
dysmenorrhea, dyspareunia, dyschezia
URO involvement include – frequency, Behavioral/Diet Modification
dysuria and hematuria
Oral Pharmacologic Therapy
Diagnostic Laparoscopy – Gold standard
with “Powder Burn” lesions Intravesical Therapy
Combined procedure with cystoscopy, Pelvic Floor Physical Therapy
hydrodistention for complicated patient Surgical Therapy
history
Endometriosis – Laparoscopic Management of PBS/IC
Appearance
Behavioral Therapy for PBS/IC
Diet Avoidance Therapy
Acidic fruits, spicy foods, processed meats,
caffeine, alcohol, preservatives.
Bladder Retraining
Relaxation Techniques
Coping Strategies
Powder burn lesions of the
uterosacral ligaments
Chocolate cyst of the ovary
11

18. Management of PBS/IC Management of PBS/IC
Pharmacologic Therapy Pelvic Floor Physical Therapy
Antidepressants (Amitriptyline) Reports of symptom reduction using myofascial
trigger point release therapy using
Anticonvulsants (Gabapentin,Pregabalin)
nonstandardized techniques and no controls.
Antihistamines (Hydroxyzine)
Immunosuppressants (Cyclosporin,Cellcept)
NIDDK/NIH protocol ongoing thru the ICCRN
Analgesics/Narcotics network to standardize technique and include
GAG Layer Replacement (PPS) sham control.
Management of PBS.IC Sacral nerve neuromodulation
Intravesical Agents
BCG: failed NIDDK RCT Sacral Nerve
Modulation is a
DMSO/Heparin/Solumedrol
promising surgical
Hyaluronan: failed 2 large US RCT treatment for IC/PBS
Intravesical Elmiron: 2 small positive trials* however remains still
investigational
RTX: failed US phase 2 trial; recent trials
Level 2 evidence
inconclusive**
Grade D
Alkalanized lidocaine solutions recommendation
**Urol Int 2007;78(1):78-81
*Bade, J Urol, 163S:60, 2000
Hinyokika Kiyo 2006; 52(12):911-3
Davis, J Urol, 179:177-185, 2008
J. Urol, 173:1590, 2005
Intradetrusor: Botulinum A Toxin Sacral Neuromodulation
One year follow-up of open label study in BPS/IC Urgency frequency long term followup
n=15 (200u in 20cc, trigone, lateral walls)
At 3 months, 86% had pain relief
Elhilali: N=22; 45% persistent improvement
Elhilali:
At 5 months 26% had pain relief after successful test stimulation 5-17 year f/u
5-
At 12 months pain recurred in all patients 2 ic patients no improvement
9 patients had dysuria post treatment persisting 1-5 Comiter had 17 of 25 success in IC at 14
months
months in those permanently implanted
3 pts needed CIC after Rx, 2 at 3 mos and 1 at 5
mos
Urol 65:1114, 2005
J. Urol 169:1369, 2003
Giannantoni et al: J Urol, 179:1031, 2008
12

19. Level 4 evidence
•Bladder augmentation
Grade C recommendation
SURGERY FOR PBS / IC
Cystoplasty
Cystoplasty with supratrigonal resection
Cystoplasty with subtrigonal cystectomy
Surgical options should be considered only
No outcome difference among bowels segments when all conservative treatment failed.
except for dysuria associated with gastric tissue The patient should be informed of all aspects
substitution.
Weak evidence that cystoplasty with supratrigonal of surgery and understand consequences
resection is superior. and potential side effects of surgical
Subtrigonal cystectomy with cystoplasty has no intervention.
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
Total cystectomy and urethrectomy
IC/PBS: ALGORITHM
Suspect PBS
Level of evidence: 4 History/Physical Hematuria,
Grade of recommendation: C UA, Culture, Infection, Appropriate
Cytology + Cytology, work-up
x
Sx questionnaire H + PE finding
al
Ty
ic
pi
yp
ca
Urinary diversion with or without cystectomy and orthotopic At
lH
Treatment
x
continent bladder may be the ultimate option for refractory Education GYN referral
Diet modification UDS
patients. Analgesics Imaging studies
Continent diversion may have better cosmetic and life style GI work-up
Inadequate response Endometriosis,
outcome but recurrence of IC in the pouch is a real BOO,
Calculi, etc.
possibility. Elavil PBS
There is no literature evidence of any advantage of Failed
Improved
continent surgery d Hydrodistention Oral agents (PPS)
ile
Fa Inadequate Intravesical Tx
+/- Laparoscopy response
ed Pelvic floor rehab
Follow & Support ov
pr
Im
Time for a cystectomy? IC/PBS: ALGORITHM
Oral agents
Intravesical Tx
Pelvic floor rehab
Inadequate response
Research Protocols
Neuromodulation
Pain Clinic
Improved
Follow Failed Consider
You’ve got to ask yourself the & Support Cystectomy
question, “Do you feel lucky?”
13

20. Broad description of symptoms that Description is broad:
warrant further investigation High sensitivity
to detect bladder disease Low specificity
IC, PBS/IC, BPS/IC, BPS Diagnosis or exclusion of a
confusable disease as
the cause of the
bladder-related
symptoms
Increasing
What’s now?? Confirmation
specificity
and typing
What’s Next??? of PBS
High sensitivity
High specificity
Active Efforts Are Underway PUGO/IASP TAXONOMY
Definition
Nomenclature
Classification Axis 1: Region
ICA Axis 2: Symptom
NIDDK Axis 3: End Organ (history, examination,
investigation)
ESSIC
Axis 4: Referral Characteristics
Axis 5: Temporal Characteristics
ICICJ
Axis 6: Character
Pan Asian IC Association
Axis 7: Associated Symptoms
IASP and PUGO
Axis 8: Psychological Symptoms
New Classification and
Nomenclature
Interstitial cystitis
Bladder pain syndrome
IASP: International Association for the Urological
Study of Pain Pelvic pain syndrome
Proposal from PUGO: Pain of Urogenital Chronic pelvic pain
Origin
Scheduled to be presented August 2008
at Glasgow Meeting of IASP
14

21. Oxford Evidence Based Analysis
PBS becomes BPS, or does it? 2008: what works
Bladder pain syndrome
3 therapies supported by high level of
Urethral pain syndrome evidence in the literature
Prostate pain syndrome (formerly CPPS Amitriptyline, DMSO, Cimetidine
EAU-EBU Update Series 4(2006) 47-61
type 3) (formerly nonbacterial
Everything else is really “expert” opinion
prostatitis)
Cyclosporine clinical trials are extremely
Scrotal pain syndrome interesting; ? After rebound after Rx?
Testicular, epididymal, vasal pain J. Urol. 1996, 155:159-163
syndromes J. Urol. 2004, 171: 2138-2141
Penile pain syndrome J. Urol. 2005, 174: 2235-2238
ESSIC Classification of BPS
CYSTOSCOPY WITH HYDRODISTENTION
General Considerations
Not Done Normal Glomerulati Hunner
ons Lesion
• Treatments are empiric as cause is unknown
Not XX 1X 2X 3X • Symptoms can be controlled with one or
PBS IC variety of treatments in majority of patients
Done PBS IC
BIOPSY Normal XA 1A 2A 3A • Little evidence that treatment does more
PBS IC IC
PBS than influence symptomatic expression of
Inconclus XB 1B 2B 3B IC
PBS
ive PBS IC IC
• 50% incidence of remission (8 month
Positive XC 1C 2C IC 3C duration) unrelated to specific treatment
IC IC IC
Nordling J and van de Merwe JP. ESSIC web site, Accessed September 2006.
IC/PBS: RX Research
ICCRN Trials: results later this year
More Cautions
Trial 1
Amitriptyline plus behavioral modification • Patients can be victims of unorthodox
vs behavioral modification alone in newly
diagnosed PBS patients
providers, untested therapies, unproven
surgical procedures
Trial 2
• Few treatments have been subjected to
Cellcept® vs placebo in refractory IC
patients placebo-controlled trial
12-week treatment, then 12-week follow • Need for skepticism
up
Trial 3
Pelvic floor physical therapy vs placebo
15

22. Assessing Treatment Results
A Multi-disciplinary Approach to
• Placebo effect + natural history + regression
to the mean = high rates of good outcomes the Study of Chronic Pelvic Pain
• Caution: statistical versus clinical Syndromes: The MAPP Research
significance Network
• “A difference to be a difference must make
a difference” Gertrude Stein
To appear summer 2008
Current Pathways
Bladder Pain Syndrome/ Primary Objectives of the MAPP-I
Interstitial Cystitis
• Conduct basic and clinical research studies of
IC/PBS and CP/CPPS considering these
Old Paradigm IC: New Paradigm: syndromes as systemic disorders (cross-studies of
Identify Marker Bladder Pain Syndrome/IC
Determine Pathophysiology chronic fatigue syndrome, fibromyalgia,
Treat the Pain
Modify Pathophysiology
Local Causes in Bladder irritable bowel syndrome, migraine headache
OH
OH CO2H
OH OH
OH
Prevent Centralization and vulvodynia)
HO O
O O
AcHN
HO
O O
OH HO
Ac NH
• Can co-morbid illnesses in patients with
O O
N
O
O O O
IC/PBS or CP/CPPS provide additional
H H H H
NH2 N
N
H
O
N
N
H
O
N
N
H
O
N COOH
insights into these syndromes?
New NIH Approach MAPP Research Network
Urologic Chronic Pelvic Pain
Discovery Discovery Discovery Discovery Discovery Discovery Data and
Site Site Site Site Site Site Administrative
Phenotype Phenotype Phenotype Phenotype Phenotype Phenotype Core
• Abandon “hit-or-miss” approach to Epi Epi Epi Epi Epi Epi Tissue &
Technology
selection of candidate therapies for clinical Basic Basic Basic Basic Basic Basic
Core
Basic Phenotype Epi Basic
trials Epi Epi Phenotype
• Integrate both basic and clinical research
• Knowledge about “disease mechanisms” External Advisory Trans-NIH Pain
used to identify targets for suitable agents to NIDDK Committee Advisory Group
be tested in future clinical trials
16

24. IC/PBS: ALGORITHM
Suspect PBS
History/Physical Hematuria,
UA, Culture, Infection, Appropriate
Cytology + Cytology, work-up
x
Sx questionnaire l H + PE finding
Ty
p
i ca
ic
a
yp
At
lH
x
Treatment
Education GYN referral
Diet modification UDS
Analgesics Imaging studies
GI work-up
Inadequate response Endometriosis,
BOO,
Calculi, etc.
Elavil PBS
Failed
Improved
ed Hydrodistention Oral agents (PPS)
F ail Inadequate Intravesical Tx
d +/- Laparoscopy response
ve Pelvic floor rehab
Follow & Support ro
I mp

25. IC/PBS: ALGORITHM
Oral agents
Intravesical Tx
Pelvic floor rehab
Inadequate response
Research Protocols
Neuromodulation
Pain Clinic
Improved
Follow Failed Consider
& Support Cystectomy

26. 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

27. 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

28. 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,

29. 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

30. 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