1. 1 Painful Bladder Syndrome/Interstitial Cystitis: A New Paradigm Emerging C. Lowell Parsons Professor of Surgery/Urology School of Medicine University of Ca. San Diego C. Lowell Parsons Professor of Surgery/Urology School of Medicine University of Ca. San Diego 1

2. 2 Major Themes PBS/IC Misdiagnosis is Common Epithelial Damage and Urinary Potassium Associated with PBS/IC Prevalence Better Appreciated Now PBS/IC Case Studies PBS/IC Misdiagnosis is Common Epithelial Damage and Urinary Potassium Associated with PBS/IC Prevalence Better Appreciated Now PBS/IC Case Studies

3. 3 PBS/IC History In 1980 little known about pathogenesis PBS/IC was only known to exist and only the very severe form was recognized and diagnosed Only hypothetical causes suggested, e.g. maybe infectious or autoimmune PBS/IC often misdiagnosed as UTI, OAB, gynecologic problem In 1980 little known about pathogenesis PBS/IC was only known to exist and only the very severe form was recognized and diagnosed Only hypothetical causes suggested, e.g. maybe infectious or autoimmune PBS/IC often misdiagnosed as UTI, OAB, gynecologic problem

4. 4 What is PBS/IC ? A disease of the urinary bladder It causes frequency and urgency of urination, pelvic pain and urinary incontinence Can flare suddenly after sexual activity Causes pain with sex often first symptom Flares the week before the menstrual cycle May flare with allergy season A disease of the urinary bladder It causes frequency and urgency of urination, pelvic pain and urinary incontinence Can flare suddenly after sexual activity Causes pain with sex often first symptom Flares the week before the menstrual cycle May flare with allergy season

5. 5 PBS/IC Symptoms/Lower Urinary Symptoms Frequency, Urgency primarily bladder symptoms Dysuria is a urethral symptom Pain from bladder refers anyplace in pelvis, Labia, Scrotum, Perineal, Abdominal, Medial thighs. This referred pain confuses origin Frequency, Urgency primarily bladder symptoms Dysuria is a urethral symptom Pain from bladder refers anyplace in pelvis, Labia, Scrotum, Perineal, Abdominal, Medial thighs. This referred pain confuses origin

6. 6 What is PBS/IC ? PBS/IC may begin at age 16-20 with frequency Symptoms may become very severe and debilitating Flares PBS/IC may begin at age 16-20 with frequency Symptoms may become very severe and debilitating Flares

7. 7 Where Does Interstitial Cystitis Begin? SEVERITY OF SYMPTOMS: A SPECTRUM OF DISEASE “Recurrent UTI” misdiagnosis NIH Cases Advanced Interstitial Cystitis Mild/Moderate Interstitial Cystitis GYN Dx’s “Urethral Syndrome” “Overactive Bladder” Prostatitis

8. 8 Overlap Between OAB and PBS/IC Slide courtesy of GR Sant, MD. Frequency Urgency Pain Frequency Urgency Pain Painful Bladder Syndrome/

9. 9 PUF Diagnostic Questionnaire for PBS/IC Symptoms Developed to identify PBS/IC patients Also determines disease severity Widely used by Urologists and Gynecologists Validated by Kushner and Moldwin 2006 Developed to identify PBS/IC patients Also determines disease severity Widely used by Urologists and Gynecologists Validated by Kushner and Moldwin 2006

10. 10 PUF: Pelvic Pain and Urgency/ Frequency Patient Symptom Scale Circle the answer that best describes how you feel for each question. 01234 Symptom Score Bother Score 3-67-1011-1415-1920+ 01234+ NoneMildModerateSevere NeverOccasionallyUsuallyAlways NeverOccasionallyUsuallyAlways NeverOccasionallyUsuallyAlways NeverOccasionallyUsuallyAlways MildModerateSevere NeverOccasionallyUsuallyAlways MildModerateSevere NeverOccasionallyUsuallyAlways SYMPTOM SCORE (1, 2a, 4a, 5, 6, 7a, 8a) BOTHER SCORE (2b, 4b, 7b, 8b) How many times do you void during waking hours? a. How many times do you void at night? b. If you get up at night to void, to what extent does it usually bother you? Are you currently sexually active? YES _____ NO_____ a. If you are sexually active, do you now have or have you ever had pain or urgency to urinate during or after b. Has pain or urgency ever made you avoid sexual intercourse? Do you have pain associated with your bladder or in your pelvis, vagina, lower abdomen, urethra, perineum, testes, or scrotum? Do you still have urgency shortly after urinating? a. When you have pain, is it usually—? b. How often does your pain bother you? a. When you have urgency, is it usually—? b. How often does your urgency bother you? TOTAL SCORE (Symptom Score + Bother Score) = sexual intercourse? 1 1 2 2 3 3 4 4 5 5 6 6 8 8 7 7

11. 11 PBS/IC Prevalence Higher Original estimates in the 1980s only 40K in US With PUF Questionnaire Rosenberg and Hazzard (2005) found prevalence much higher Rand Study also validates much higher PBS/IC prevalence of 3-8 million in US PBS/IC estimated 3-10 million in US Original estimates in the 1980s only 40K in US With PUF Questionnaire Rosenberg and Hazzard (2005) found prevalence much higher Rand Study also validates much higher PBS/IC prevalence of 3-8 million in US PBS/IC estimated 3-10 million in US

12. 12 The Role of the Epithelium in the Pathogenesis of PBS/IC

13. 13 Bladder Epithelium Damaged Cystoscopy reveals bladder damage Normal Healthy Bladder PBS/IC Bladder with visible damage

14. 14 Mucus GAG Layer Regulates Epithelial Permeability GAG: Glycosaminoglycan

15. 15 Epithelial Mucus GAG Layer Water hydrates GAG Layer Schematic Micrograph Schematic Micrograph

16. 16 The Role of Urinary Potassium in the Generation of Bladder Symptoms and Tissue Injury

17. 17 Healthy bladders sequester bladder contents Healthy bladders prevent leakage of contents (% instilled urea) Protamine damage allows leakage Heparin treatment mostly restores bladder’s ability to sequester contents Healthy bladders prevent leakage of contents (% instilled urea) Protamine damage allows leakage Heparin treatment mostly restores bladder’s ability to sequester contents *SG&O 1990 % Leak of Solute Urea

18. 18 PBS/IC Patients have Damaged Bladders that Leak Normals=41 IC=56 J.Urol 1991 % Leak of Solute Urea

19. 19 Mucus K + Vessels An _ Nerve K + Muscle Fate of Urinary Potassium Mast cell Prostate K +

20. 20 The Etiology of Symptoms in the Lower Urinary Tract

21. 21 PBS/IC Differential Diagnosis Recurrent UTI Urethral Syndrome Neurogenic Bladder Detrusor instability, OAB Pelvic Floor dysfunction Radiation, Cytoxan cystitis Vaginitis Tb, Schistosomiasis PBS/IC

22. 22 Diagnosis by Tradition, Sex, Specialist, Sub-committee 25 yr. Old female with 12 voids per day, flare of urgency, pain with sex, intermittent dysparuenia, Neg U/A: Sees GU- Recurrent UTI Sees Gyn- Endometriosis, yeast infection 25 yr. Old Male with 12 voids per day, Flare of urgency, pain with sex, intermittent painful ejaculations, Neg U/A: Prostatitis 25 yr. Old female with 12 voids per day, flare of urgency, pain with sex, intermittent dysparuenia, Neg U/A: Sees GU- Recurrent UTI Sees Gyn- Endometriosis, yeast infection 25 yr. Old Male with 12 voids per day, Flare of urgency, pain with sex, intermittent painful ejaculations, Neg U/A: Prostatitis

23. 23 PBS/IC/Prostatitis in Men

24. 24 Potassium Sensitivity in Prostatitis Patients GroupNKCl Positive ________________________________ Prostatitis*4134 (83%) Normals*430 Patients**3126 (84%) *Parsons Et al Journal of Urology Sept. 2002 **Hassan et al Int Journ Urol Aug 2007 GroupNKCl Positive ________________________________ Prostatitis*4134 (83%) Normals*430 Patients**3126 (84%) *Parsons Et al Journal of Urology Sept. 2002 **Hassan et al Int Journ Urol Aug 2007

25. 25 Unifying Hypothesis: Common Symptoms of Lower Urinary Tract Lower Urinary Epithelial Dysfunction has increased urothelial permeability Potassium diffusion into bladder wall causes symptoms: Pain, Muscle Spasms and tissue damage PBS/IC, OAB, CP/CPPS, Urethral Syndrome, UFS, Recurrent UTI’s, Gyn CPP, V/V PBS/IC is merely the severe form of this disease Lower Urinary Epithelial Dysfunction has increased urothelial permeability Potassium diffusion into bladder wall causes symptoms: Pain, Muscle Spasms and tissue damage PBS/IC, OAB, CP/CPPS, Urethral Syndrome, UFS, Recurrent UTI’s, Gyn CPP, V/V PBS/IC is merely the severe form of this disease

26. 26 Therapy Principles for PBS/IC Correct Epithelial Dysfunction Inhibit Neural Hyperactivity Control Allergies Correct Epithelial Dysfunction Inhibit Neural Hyperactivity Control Allergies

27. 27 Therapies for PBS/IC Discovery that Heparin and PPS (Elmiron ® ) repaired experimentally injured human and rodent bladders led to following treatments Elmiron ® - oral drug approved in 1997 Urigen developing URG101 - a combination of intravesical Heparin and alkalinized Lidocaine for immediate relief of bladder pain and restoration of bladder mucus GAG layer Discovery that Heparin and PPS (Elmiron ® ) repaired experimentally injured human and rodent bladders led to following treatments Elmiron ® - oral drug approved in 1997 Urigen developing URG101 - a combination of intravesical Heparin and alkalinized Lidocaine for immediate relief of bladder pain and restoration of bladder mucus GAG layer

28. 28 PBS/IC Case Studies

29. 29 GU Pediatric Case Study (#1) 9 yr old female taken out of diapers age 5 but had several incontinent episodes per day Main symptoms are severe urgency, chronic lower abdominal pain that is increasing, intense symptoms flares treated as UTI’s Some urine cultures positive for E. coli, many negative culture reports, cystoscopy- normal UO’s, cystitis cystica 9 yr old female taken out of diapers age 5 but had several incontinent episodes per day Main symptoms are severe urgency, chronic lower abdominal pain that is increasing, intense symptoms flares treated as UTI’s Some urine cultures positive for E. coli, many negative culture reports, cystoscopy- normal UO’s, cystitis cystica

30. 30 GU Pediatric Case Study (#1) What is diagnosis? Traditional Urology Diagnosis? What to do for therapy? After this workup a urinary diversion was recommended and patient self referred to UCSD What is diagnosis? Traditional Urology Diagnosis? What to do for therapy? After this workup a urinary diversion was recommended and patient self referred to UCSD

31. 31 GU Pediatric Case Study (#1) Used Therapeutic solution containing Heparin+lidocaine+NaBicarb Immediate relief of 75%+ of symptoms Daily after 3 weeks of solution plus Elmiron- no incontinence, urge and pain 75%+ gone; Patient wanted to cath herself and did so 3 months later, no urge or pain no incontinence for 2 months 5 months after Rx only oral Elmiron Used Therapeutic solution containing Heparin+lidocaine+NaBicarb Immediate relief of 75%+ of symptoms Daily after 3 weeks of solution plus Elmiron- no incontinence, urge and pain 75%+ gone; Patient wanted to cath herself and did so 3 months later, no urge or pain no incontinence for 2 months 5 months after Rx only oral Elmiron

32. 32 Urology Case Study (#2) 21 yr old female referred with Dx of recurrent “UTI” 3 years of 5-6 “UTI’s” per year Pain and Symptoms during and after sex, now tends to avoid sex Antibiotics make her Better, Last two C&S’s sterile, She voids 12 per day, 1 x nocturia when “uninfected” U/A- no RBCs, no WBC’s, no bacteria. What is her diffential diagnosis 21 yr old female referred with Dx of recurrent “UTI” 3 years of 5-6 “UTI’s” per year Pain and Symptoms during and after sex, now tends to avoid sex Antibiotics make her Better, Last two C&S’s sterile, She voids 12 per day, 1 x nocturia when “uninfected” U/A- no RBCs, no WBC’s, no bacteria. What is her diffential diagnosis

33. 33 GU Bladder Pain: PBS/IC Dyspareunia Perimenstrual flare Flares after sex Pain (lower abdomen, vulva, urethra, vagina, medial thighs, perineum) Voiding symptoms GU Bladder Pain: PBS/IC Dyspareunia Perimenstrual flare Flares after sex Pain (lower abdomen, vulva, urethra, vagina, medial thighs, perineum) Voiding symptoms Gyn Pelvic Pain: Dyspareunia Menstrual/ perimenstrual flare Flares after sex Pain (lower abdomen, vulva, urethra, vagina, medial thighs, perineum) Voiding symptoms Pelvic Pain Symptoms

34. 34 Gynecology Case Study (#3) 25 yr. Old female presents with Chronic dyspareunia for 6 years, progressing Labial pain and lower abdominal pain (increases week before menses) No vaginal discharge, good health What is her differential Diagnosis? 25 yr. Old female presents with Chronic dyspareunia for 6 years, progressing Labial pain and lower abdominal pain (increases week before menses) No vaginal discharge, good health What is her differential Diagnosis?

35. 35 Major Take Aways PBS/IC Misdiagnosis is Common Pain is referred, flares PBS/IC can be mild to severe symptoms Prevalence Better Appreciated Now PUF Questionnaire for better PBS/IC diagnosis RAND and other studies validate much larger PBS/IC prevalence PBS/IC Misdiagnosis is Common Pain is referred, flares PBS/IC can be mild to severe symptoms Prevalence Better Appreciated Now PUF Questionnaire for better PBS/IC diagnosis RAND and other studies validate much larger PBS/IC prevalence