Interstitial Cystitis/Painful Bladder
Syndrome: A Primer and an Update
                                                   ...
Interstitial Cystitis/Painful Bladder
Syndrome: A Primer and an Update
                                                   ...
Meeting Disclaimer
Regarding materials and information received, written or otherwise, during the 2008 American Urological...
2008 AUA Annual Meeting


93 IC    Interstitial Cystitis / Painful Bladder Syndrome – A Primer and an Update


5/20/2008  ...
Disclosure of Off-Label Uses

The audience is advised that this continuing medical education activity may contain referenc...
Bladder Pain Syndrome / Interstitial Cystitis A Primer and an Update 2008

                                   Philip Hanno...
The Analects of Confucius, Book 13, Verse 3 (James R.
                                                            Ware, tr...
Painful Bladder Syndrome/IC does
         not stand alone                                                               We...
Clinical Definition: The Aunt
Definition is a Problem                                                    Minnie (hard to d...
Revised NIDDK Criteria                                                                   Laboratory Definition:
        Pa...
Provocative Testing Definition:
Positive Potassium Test                                             Specificity of potassi...
ESSIC Proposed Definition

                                                                             Bladder Pain Syndr...
Prevalence per 100,000
                                                                                      450
         ...
IC/PBS: PHYSICAL EXAMINATION

                                                              Abdominal, Pelvic and Neurolog...
IC/PBS: DIFFERENTIAL DIAGNOSIS                                                 Diagnosis: cystoscopy

   GASTROENTEROLOGY ...
IC/PBS: Cystscopic Evaluation
                                                                                            ...
Management of PBS/IC

                                                             Primary Treatment Goals
               ...
Management of PBS/IC                                                            Management of PBS/IC

    Pharmacologic Th...
Level 4 evidence
•Bladder augmentation
                                                   Grade C recommendation
         ...
Broad description of symptoms that                        Description is broad:
                                          ...
Oxford Evidence Based Analysis
           PBS becomes BPS, or does it?                                                    ...
Assessing Treatment Results
                                                                                              ...
IC/PBS: ALGORITHM
                                 Suspect PBS



                              History/Physical          ...
IC/PBS: ALGORITHM
                    Oral agents
                  Intravesical Tx
                 Pelvic floor rehab

 ...
Interstitial Cystitis / Painful Bladder Syndrome / Bladder Pain Syndrome: The
Evolution of a New Paradigm

Evolution of a ...
1978 Messing & Stamey: Nonspecific and highly subjective symptoms of around
         the clock frequency, urgency, and pai...
Unfortunately, histopathology does not really help when it comes to defining this
symptom complex. One can have bladder bi...
and perhaps a way to define it. As of 2007, neither have her findings been replicated by
other centers, nor has a commerci...
long, complex agendas, it is useful to look at how each approached the definition of the
syndrome.
         The first of t...
Cistitis insterticial
Cistitis insterticial
Cistitis insterticial
Cistitis insterticial
Cistitis insterticial
Cistitis insterticial
Cistitis insterticial
Cistitis insterticial
Cistitis insterticial
Cistitis insterticial
Cistitis insterticial
Cistitis insterticial
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  1. 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. 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.
  3. 3. Meeting Disclaimer Regarding materials and information received, written or otherwise, during the 2008 American Urological Association Education and Research, Inc. Annual Meeting Instructional/Postgraduate MC/EC and Dry Lab Courses sponsored by the Office of Education: The scientific views, statements, and recommendations expressed in the written materials and during the meeting represent those of the authors and speakers and do not necessarily represent the views of the American Urological Association Education and Research, Inc.® Reproduction Permission Reproduction of all Instructional/Postgraduate, MC/EC and Dry Lab Courses is prohibited without written permission from individual authors and the American Urological Association Education and Research, Inc. These materials have been written and produced as a supplement to continuing medical education activities pursued during the Instructional/Postgraduate, MC/EC and Dry Lab Courses and are intended for use in that context only. Use of this material as an educational tool or singular resource/authority on the subject/s outside the context of the meeting is not intended. Accreditation The American Urological Association Education and Research, Inc. is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education (CME) for physicians. The American Urological Association Education and Research, Inc. takes responsibility for the content, quality, and scientific integrity of the CME activity. CME Credit The American Urological Association Education and Research, Inc. designates each Instructional Course educational activity for a maximum of 1.5 AMA PRA Category 1 credits™; each Postgraduate Course for a maximum of 3.25 AMA PRA Category 1 credits™; each MC Course for a maximum of 1.0 AMA PRA Category 1 credits™; each EC Course for a maximum of 2.0 AMA PRA Category 1 credits™; each MC Plus Course for a maximum of 2.0 AMA PRA Category 1 credits™; and each Dry Lab Course for a maximum of 2.5 AMA PRA Category 1 credits™. Physicians should only claim credits commensurate with the extent of their participation in the activity. Disclosure Policy Statement As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), the American Urological Association Education and Research, Inc., must insure balance, independence, objectivity and scientific rigor in all its sponsored activities. All faculty participating in an educational activity provided by the American Urological Association Education and Research, Inc. are required to disclose to the audience any relevant financial relationships with any commercial interest to the provider. The intent of this disclosure is not to prevent a faculty with relevant financial relationships from serving as faculty, but rather to provide members of the audience with information on which they can make their own judgments. The American Urological Association Education and Research, Inc. must resolve any conflicts of interest prior to the commencement of the educational activity. It remains for the audience to determine if the faculty’s relationships may influence the educational content with regard to exposition or conclusion. When unlabeled or unapproved uses are discussed, these are also indicated. Evidence-based Content As a provider of continuing medical education accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the American Urological Association Education and Research, Inc. to review and certify that the content contained in this CME activity is evidence-based, valid, fair and balanced, scientifically rigorous, and free of commercial bias.
  4. 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. Disclosures According to the American Urological Association’s Disclosure Policy, speakers involved in continuing medical education activities are required to report all relevant financial relationships with any commercial interest to the provider by completing an AUA Disclosure Form. All information from this form is provided to meeting participants so that they may make their own judgments about a speaker’s presentation. Well in advance of the CME activity, all disclosure information is reviewed by a peer group for identification of conflicts of interest, which are resolved in a variety of ways. The American Urological Association does not view the existence of relevant financial relationships as necessarily implying bias, conflict of interest, or decreasing the value of the presentation. Each faculty member presenting lectures in the Annual Meeting Instructional or Postgraduate, MC or EC and Dry Lab Courses has submitted a copy of his or her Disclosure online to the AUA. These copies are on file in the AUA Office of Education. This course has been planned to be well balanced, objective, and scientifically rigorous. Information and opinions offered by the speakers represent their viewpoints. Conclusions drawn by the audience members should be derived from careful consideration of all available scientific information. The following faculty members(s) declare a relationship with the commercial interests as listed below, related directly or indirectly to this CME activity. Participants may form their own judgments about the presentations in light of full disclosure of the facts. Faculty Disclosure Philip M. Hanno, M.D. Course Director Astellas: Consultant or Advisor Omerus: Consultant or Advisor Taiho: Meeting Participant or Lecturer Wyeth: Consultant or Advisor Watson: Meeting Participant or Lecturer David A. Burks, M.D. Astellas Pharma, US: Meeting Participant or Lecturer Glaxo-Smith-Klein Pharma, US: Meeting Participant or Lecturer
  5. 5. Disclosure of Off-Label Uses The audience is advised that this continuing medical education activity may contain reference(s) to unlabeled or unapproved uses of drugs or devices. Please consult the prescribing information for full disclosure of approved uses. Faculty and speakers are required to disclose unlabeled or unapproved use of drugs or devices before their presentation or discussion during this activity. A special AUA value for your patients: www.UrologyHealth.org is a joint AUA/AFUD patient education web site that provides accurate and unbiased information on urologic disease and conditions. It also provides information for patients and others wishing to locate urologists in their local areas. This site does not provide medical advice. The content and illustrations are for informational purposes only. This information is not intended to substitute for a consultation with a urologist. It is offered to educate the patient, and their families, in order for them to get the most out of office visits and consultations.
  6. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
  23. 23. 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
  24. 24. IC/PBS: ALGORITHM Oral agents Intravesical Tx Pelvic floor rehab Inadequate response Research Protocols Neuromodulation Pain Clinic Improved Follow Failed Consider & Support Cystectomy
  25. 25. 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
  26. 26. 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
  27. 27. 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,
  28. 28. 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
  29. 29. 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

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