1. Interstitial Cystitis and Painful Bladder Syndromes
Eric S. Rovner, M.D.
Professor of Urology
Medical University of South Carolina
Charleston, South Carolina

2. Painful Bladder Syndrome: Definition

3. Painful Bladder Syndrome: ICS Definition

4. Definition

5. ? Definition Painful Bladder Syndrome Urethral Pain Syndrome
Vulval Pain Syndrome
Vaginal Pain Syndrome
Scrotal Pain Syndrome
Pelvic Pain Syndrome
Perineal Pain Syndrome
(Interstitial Cystitis) ?

6. Definition: Where are we?
Clinical syndrome defined by symptoms of:
Urgency
Frequency
Pain
……..in the absence of any other reasonable causation.
We really have no accepted definition!!!!!!!!

7. Majority of Women With CPP Have No Obvious Etiology
Chronic Pelvic Pain (CPP)
Majority of Women With CPP Have No Obvious Etiology
39% Confirmed Diagnosis
61% Undefined Etiology
Majority of Women With CPP Have No Obvious Etiology
In this same study by Mathias et al, a majority of women (61%) had no obvious etiology for CPP. Only 39% of patients had a confirmed diagnosis of CPP.
Mathias SD, Kupperman M, Liberman RF, Lipschutz RC, Steege JF. Chronic pelvic pain: prevalence, health-related quality of life, and economic correlates. Obstet Gynecol. 1996;87:
Mathias SD et al. Obstet Gynecol. 1996;87:

8. Chronic Pelvic Pain Is Characterized by Overlapping Disease Conditions
Interstitial
Cystitis
Neuropathic
Endometriosis
Chronic
Pelvic Pain
Overlapping Disease Conditions
Vulvodynia
Pelvic floor/GI Disorders
Pelvic Infection and Adhesions
Chronic Pelvic Pain Is Characterized by Overlapping Disease Conditions
A variety of common conditions have a similar clinical presentation and cause CPP. Therefore, chronic pelvic pain is frequently difficult to diagnose accurately. Some of the most common causes of CPP include:
Interstitial cystitis
Endometriosis
Vulvodynia
GI disorders
Pelvic infection and adhesions
Recurrent UTI
Misc. inflammatory
Recurrent UTI

9. Presumptive Diagnosis
History
Physical examination
Voiding Diary
Appropriate cultures
Local cystoscopy (especially with hematuria)
Cytology in smokers and patients >40yrs

10. Definitive Diagnosis??? Urodynamics
Cystoscopy under anesthesia with hydrodistention
potentially therapeutic
Bladder biopsy
+/- if endoscopic findings abnormal
Imaging (CT/Ultrasound/MRI/VCUG)
Laparoscopy
If reasonable suspicion of endometriosis, etc.
Not usual part of Urologist w/u

11. Things that make me doubt IC Dx*
Constant pain with no relationship to either filling or voiding
No pain when first wakes up
Voiding < 7 times in 24 hours
Pain mostly occurs during voiding, suggests:
Urethral diverticulum
Internal or external sphincter dysfunction
Vulvar source of pain
*Debbie Erickson 2011

12. Key question: What happens if you try to hold your urine?*
Hurts a lot = IC/PBS
Leak urine = detrusor overactivity
“It just feels like I have to go” but can postpone= polydipsia or sensory disorder
Can’t tell: a diagnostic dilemma; urodynamics may be very helpful here
*Raz

13. “Typical” Findings
Hunners Ulcer
Glomerulations

14. Excludes tissue specific diagnoses only: No pathognomonic findings
“Typical” Pathology
Nerve hypertrophy
Detrusor mastocytosis
Nonulcerative IC
Hunner’s ulcer
Excludes tissue specific diagnoses only:
No pathognomonic findings

15. KCl Test Intravesical sensitivity to 0.4M potassium solution
80% of IC patients test positive
20% false negative rate
4% false positive rate in normals
25% false positive rate in detrusor overactivity
100% false positive rate with UTI
……is it going to change what you are going to do?

16. Potassium Sensitivity Test
Not a standard diagnostic test for IC
Opinions from recent consensus conferences:
Don’t do it*
Not mentioned**
For excellent “opposing views” debate see Journal of Urology, August 2009, p431-4
*Hanno P, Int Urogynecol J 2005
**van de Merwe JP, Eur Urol 2008

17. Serum/Urine Markers??? Antiproliferative Factor (APF) Methylhistamine
Epidermal growth factor
Insulin-like growth factor binding protein-3
IL-6
Cyclic guanosine monophosphate
Others

18. IC: Theories of Pathogenesis
Infectious/inflammatory
Reflex sympathetic dystrophy (RSD) of pelvic floor/bladder
Immune/Autoimmune
Pelvic floor dysfunction
Allergic: Mast cell involvement1
Neurogenic inflammation with substance P2
Mucosal barrier glycosaminoglycan (GAG) deficiency3,4
Other: Psychological?? (e.g. sexual abuse5)
IC: Theories of Pathogenesis
Although the exact cause of IC is unknown, there are 3 major theories as to the cause of IC:
• Mast cell activation1: Several studies have shown that increased numbers of mast cells
are present in the bladders of patients with IC. Mast cell activation and degranulation is
caused by various mediators, such as histamine, and leads to further inflammation
• Neurogenic inflammation2: Substance P (SP) is a neuropeptide secreted from nerve endings.
It modulates pain and inflammation and has been shown to trigger mast cell degranulation. A study by Pang et al showed that patients with IC had increased numbers of SP-positive nerve fibers in their bladders compared with control patients
Mucosal barrier glycosaminoglycan (GAG) deficiency3,4: The urinary epithelium is lined by
glycosaminoglycans. The GAG layer is thought to protect the bladder by creating a barrier,
which prevents bacterial adherence and the movement of urinary substances
1. Theoharides T et al. Urology. 2001;57(suppl 6A):47-55.
2. Pang X et al. Br J Urol. 1995;75:
3. Parsons CL et al. J Urol. 1990;143:
4. Parsons CL. Urology. 2003;62:
5. Peters, K et al, JU
1. Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and
experimental evidence. Urology. 2001;57(suppl 6A):47-55.
2. Pang X, Marchand J, Sant GR, Kream RM, Theoharides TC. Increased number of substance P positive nerve fibers in
interstitial cystitis. Br J Urol. 1995;75:
3. Parsons CL, Boychuk D, Jones S, Hurst R, Callahan H. Bladder surface glycosaminoglycans: an epithelial permeability
barrier. J Urol. 1990;143:
4. Parsons CL. Prostatitis, interstitial cystitis, chronic pelvic pain, and urethral symptoms share a common pathophysiology:
lower urinary dysfunctional epithelium and potassium recycling. Urology. 2003;62:

19. Disparate triggers: Factors Associated With Flares of IC1-5
Sexual intimacy/intercourse1,4
Premenstrual/periovulatory1-4
Allergies3
Diet
Physical, emotional stress5
Pelvic floor spasm4
Symptoms of IC Worsen During Flares
Many women experience worsening symptoms during IC flares.1-5 There are various
factors that can provoke symptom flares including:
Sexual intimacy/intercourse1,4
Premenstrual/periovulatory1-4
Allergies3
Diet
Physical, emotional stress5
Pelvic floor spasm4
1. Parsons CL, Dell J, Stanford EJ, Bullen M, Kahn BS, Willems JJ. The prevalence of interstitial cystitis in gynecologic patients with pelvic pain, as detected by intravesical potassium sensitivity. Am J Obstet Gynecol. 2002;187:
2. Parsons CL. Interstitial cystitis. Int J Urol. 1996;3:
3. Parsons CL. Interstitial cystitis: epidemiology and clinical presentation. Clin Obstet Gynecol. 2002;45:
4. Parsons CL, Bullen M, Kahn BS, Stanford EJ, Willems JJ. Gynecologic presentation of interstitial cystitis as detected by intravesical potassium sensitivity. Obstet Gynecol. 2001;98:
5. Parsons CL. Evaluating and Managing Interstitial Cystitis. Englewood Cliffs, NJ: University Research Associates Rx, Inc; 1997:1-46.
1. Parsons CL et al. Am J Obstet Gynecol. 2002;187:
2. Parsons CL. Int J Urol. 1996;3:
3. Parsons CL. Clin Obstet Gynecol. 2002;45:
4. Parsons CL et al. Obstet Gynecol. 2001;98:
5. Parsons CL. Evaluating and Managing Interstitial Cystitis. University Research Associates Rx, Inc; 1997:1-46.

20. Disparity in IC Treatments…..
All are efficacious…or not ????
Supportive
Behavior/Dietary/PFE’s
Drugs:
Elmiron, Elavil, L-Arginine, anti-inflammatories, antihistamines, etc.
Hydrodistention/Laser ulcers
Intravesical Therapy:
DMSO, BCG, Heparin, Chlorpactin, etc.
Surgery
Radical surgery

21. NIH Trials
Elmiron/hydroxyzine
BCG
Immune modulators
Other

22. Can the constellation of data, observations, and opinions about IC be reconciled into one coherent pattern?

23. Unified Field Theory: All Pelvic Pain Should Ultimately be Explainable by Some Underlying Unity

24. IC “unified field theory”*
*Hanno

25. Proposed pathogenesis of IC
Bladder insult
Epithelial layer damage
Failure to repair
Antiproliferative
Factor secreted by
Epithelial cells
Keay
Leak into
interstitium
Immunogenic and
allergic responses
This slide summarizes the possible events which are believed to be involved in the pathogenesis of IC and the progression of the disease. When initially bladder epithelium is damaged by some kinds of injury or insults, epithelial barrier is compromised. High potassium in urine can then penetrate into the submucosal layer.
These tissue reactions can interact and enhance each other, thereby leading to more injury in the baldder tissue.
Mast cell activation and
histamine release
Activation of C-fibers and
release of substance P
More injury
Naoki Yoshimura

26. Pharmacological treatment of IC (1)
Bladder insult
MUCOSAL SURFACE PROTECTION
Epithelial layer damage
Leak into
interstitium
Immunogenic and
allergic responses
The first line therapies of IC consist of those which can protect and possibly repair damaged bladder epithelial surface.
Mast cell activation and
inflammatory mediators
Activation of C-fibers and
release of substance P
More injury

27. Pharmacological treatment of IC (2)
Bladder insult
Antihistamine
therapy
Epithelial layer damage
Leak into
interstitium
Immunogenic and
allergic responses
The next option for IC treatment is targeting histamine released from infiltrated mast cells
Mast cell activation and
inflammatory mediators
Activation of C-fibers and
release of substance P
More injury

28. Pharmacological treatment of IC (3)
Bladder insult
Epithelial layer damage
Tricyclic
antidepressant
Leak into
interstitium
Immunogenic and
allergic responses
Trycyclic antidepressant is also often used drug for the IC treatment. The mechanism of action of this agent is multimodal. It can suppress inflammatory responses and also suppress activation of C-fibers
Mast cell activation and
inflammatory mediators
Activation of C-fibers and
release of substance P
More injury

29. ? ? Pharmacological treatment of IC (4) Intravesical DMSO
Bladder insult
Epithelial layer damage
Intravesical
DMSO
Leak into
interstitium ? ?
Immunogenic and
allergic responses
Mast cell activation and
inflammatory mediators
Activation of C-fibers and
release of substance P
More injury

30. Pharmacological treatment of IC (others)
Bladder insult
Epithelial layer damage
BCG
Cyclosporin
Leak into
interstitium
Immunogenic and
allergic responses
Mast cell activation and
inflammatory mediators
Activation of C-fibers and
release of substance P
More injury

31. To Every Complicated Question There is an Answer that is Simple, Satisfying, and Wrong
Winston Churchill

32. YOU Mental supportive care Physiotherapy GYN / GU GI Pain management
Rheumatology
Pain management