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

Painful Bladder Syndrome: Definition

Painful Bladder Syndrome: ICS Definition

Definition

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

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!!!!!!!!

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;87:321-327. Mathias SD et al. Obstet Gynecol. 1996;87:321-327.

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

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

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

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

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

“Typical” Findings Hunners Ulcer Glomerulations

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

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?

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

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

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;75:744-750. 3. Parsons CL et al. J Urol. 1990;143:139-142 4. Parsons CL. Urology. 2003;62:976-982. 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;75:744-750. 3. Parsons CL, Boychuk D, Jones S, Hurst R, Callahan H. Bladder surface glycosaminoglycans: an epithelial permeability barrier. J Urol. 1990;143:139-142. 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;62:976-982.

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;187:1395-1400. 2. Parsons CL. Interstitial cystitis. Int J Urol. 1996;3:415-420. 3. Parsons CL. Interstitial cystitis: epidemiology and clinical presentation. Clin Obstet Gynecol. 2002;45:242-249. 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;98:127-132. 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;187:1395-1400. 2. Parsons CL. Int J Urol. 1996;3:415-420. 3. Parsons CL. Clin Obstet Gynecol. 2002;45:242-249. 4. Parsons CL et al. Obstet Gynecol. 2001;98:127-132. 5. Parsons CL. Evaluating and Managing Interstitial Cystitis. University Research Associates Rx, Inc; 1997:1-46.

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

NIH Trials Elmiron/hydroxyzine BCG Immune modulators Other

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

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

IC “unified field theory”* *Hanno

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

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

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

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

? ? 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

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

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

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