Update on

Matthew A. Barker, M.D., F.A.C.O.G Assistant Professor Departments of Obstetrics & Gynecology & Internal Medicine SSOM of The University of South Dakota

Director of Female Pelvic Medicine and Reconstructive Surgery Avera McKennan Hospital & University Health Center Avera Urogynecology Disclosures

• Speaker Astellas/GSK • Speaker Pfizer Objectives

• Understand the definition of Interstitial Cystitis/Bladder Pain Syndrome.

• Review how to diagnosis Interstitial Cystitis/Bladder Pain Syndrome.

• Review the current management and treatment of Interstitial Cystitis/Bladder Pain Syndrome. History

• 1836: Earliest published report by Philadelphia surgeon Parrish in his textbook – Documented a syndrome of paroxysmal frequency, urgency, and pelvic pain – “tic doloureux of the bladder” • 1887: Skene coined the term “interstitial cystitis” to describe this urinary syndrome. • 1915: Hunner described red bleeding area high on bladder wall in patients with severe urinary urgency, frequency, and pelvic pain.

Hanno et al. Med Clin N Am 2011 Definition

• NIH-NIDDK Criteria: -Bladder pain or urinary urgency AND -Glomerulations or Hunner’s ulcers on /hydrodistension AND -none of the exclusions listed: Awake cystometric capacity > 350ml using a fill rate of 30-100 ml/min Absence of intense urge to void at 100ml gas or 150 ml liquid Involuntary detrusor contractions on cystometry Urinary frequency less than 8 voids per day Absence of nocturia Duration of symptoms less than 9 months Age less than 18 years Cystitis, Prostatitis, vulvitis, or vaginitis Bladder, uterine, cervical, vaginal, or urethral cancer Bladder or lower ureteral calculi Urethral diverticulum

Wein, AJ, Hanno, PM, Gillenwater, JY. In: Interstitial Cystitis: An introduction to the problem. Hanno PM, Staskin DR, Krane RJ, Wein AJ, Interstitial Cystitis: Springer- Verlag, 1990 Definition

• ICS Definition(2002): 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 or other obvious pathology.

• European Society Definition (2006): symptom of chronic pain related to the accompanied by at least one urinary symptom such as daytime or nighttime frequency, AND exclusion of confusable diseases as the cause of the symptoms, AND cystoscopy with hydrodistension and biopsy if indicated. Abrams et al. Neurourol Urodyn 2002; van de Merwe et al. Eur Urol 2008 Definition

• AUA guidelines • Interstitial cystitis/bladder pain syndrome (IC/BPS) “An unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated lower urinary tract symptoms of more than 6 weeks duration, in the absence of infection or other identifiable causes.”

Hanno & Dmochowski Neuro Urodynam 2009; Hanno PM et al. J Urol 2011 Prevalence & Epidemiology

• Difficult to know due to • “True Prevalence”: determined when a strict lack of uniform diagnostic diagnostic criteria and a criteria and universal gold standard is available marker. for the diagnosis. • Estimate 30/100,000 in US, 1.2/100,000 in Japan • Poor QOL with clinical depression present in • More common in women 68% of patients. (10:1), Caucasians • Average age at diagnosis • Average IC/BPS patient 40-50 years is symptomatic for 5 years before diagnosis.

Teicheman & Parsons Urol 2007 Epidemiology

• Chronic pelvic pain affects more than 9 million women in US • Accounts for 12% of outpatient GYN referrals • 12-35% may have no detectable pathology on laparoscopy • Clemons et al (2002) performed cystoscopy with hydrodistention on 45 women undergoing laparoscopy for pelvic pain • 38% met diagnosis for IC • Parsons et al (2002): • 81% of women with chronic pelvic pain had positive potassium chloride test Etiology • Changes in urothelial permeability • Increased mast cell activity • Neuro-immune abnormalities • Neuroplasticity of the nervous system • Infectious causes • Generalized somatic disorder

• Complex & Unknown

Associaterd syndromes: IBS Chronic Fatigue Hanno P et al. Neuro Urodynam 2010 Fibromyalgia Etiology Etiology

• GAG layer deficiency

Source: Urologic Nursing, 2007; 27(1) Pathology

• No clear pathologic features in bladder biopsies. • As a group, higher incidence and degree of Campbell-Walsh 9th Ed. denuded epithelium, ulceration and submucosal . Presentation

• Variable • Best viewed as a continuum. • Pain • Symptoms begin as mild • Urgency and intermittent and become more severe as • Frequency the disease progresses. • Nocturia • Pain becomes dominant symptom with time and • Dyspareunia may impair physical, professional and personal life. Signs & Symptoms •Diagnosis of Exclusion! •Numerous conditions have overlapping symptoms. •Differential Diagnosis •Carcinoma in situ •Infection (UTI, STIs) •Radiation changes • •Urethral diverticulum • • •Chronic pelvic pain •Endometriosis •Vulvar vestibulitis •Vaginitis •Irritable bowel syndrome •Prolapse •Genital cancers •Pudendal nerve entrapment •Levator ani muscle pain

French et al. Am Fam Physician 2011 Diagnosis

• “Men or women with an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes.”

Hanno & Dmochowski Neuro Urodynam 2009 Diagnosis: History

• Suprapubic pain • Tools: • Bladder filling pain – Voiding diary – Volume/Frequency • Urgency/Frequency chart • Nocturia – Questionnaires • Pelvic pain/ • O’Leary-Sant • University of Wisconsin dysmenorrhea/ • Pelvic Pain and dyspareunia Urgency/Frequency Patient Symptom Scale • Pain in labia, vagina, or (PUF) • None validated as definitive diagnostic • Ask about abuse tool. • Associated conditions Yoost et al. J Pediatr Adolesc Gynecol 2011 Diagnosis: Physical Exam

• Abdominal & Back Exam • Pelvic Exam – Localize pain • Q-tip test/Anterior vagina • Pelvic floor muscle spasms • Rectal spasms • Suprapubic pain – Evaluate for – Assess for Atrophy – Vaginal and urethral cultures – Prolapse assessment – Rectovaginal exam – Neurologic exam Diagnostic Tests

• Lab tests -UA microscopy & culture - cytology -Post void residual • Potassium Sensitivity Test • Anesthetic Bladder Challenge • Radiologic tests -CT scan, Pelvic , VCUG, MRI Urodynamics

• Used to exclude detrusor overactivity or when diagnosis is in doubt. • Evaluates bladder capacity and compliance • Not considered to have a role in diagnosis of IC/BPS • No specific urodynamic parameter or specific symptoms can predict a positive KCl test in patients with frequency-urgency syndrome or IC. Hanno PM et al. J Urol 2011 Diagnosis - Urinary markers

• Several substances have been suggested as markers for IC/BPS. • Ease, convenience, and noninvasiveness of testing has made this a desirable avenue for research. • Erickson et al. Urol 2001: – Antiproliferative factor (APF), heparin-binding epidermal growth factor-like growth factor, epidermal growth factor, and interleukin-6 differed significantly between IC/BPS patients and controls • Logadottir et al J Urol 2004: – Nitric oxide is significantly higher in urine of patients with bladder ulcer than those without ulcers. Cystoscopy

• Not necessary for diagnosis! • Use to evaluate . • Diagnostic & Therapeutic • Hydrodistension -Bladder filled under gravity at 80cm H2O under and held for 2 minutes at maximal capacity. -Reinsert cystoscope and look for glomerulations, ulcers and linear cracking. -Biopsies can be taken. Hanno PM et al. J Urol 2011 Cystoscopy Treatment

• Early identification and treatment to help prevent progression of disease. • Need to approach as two disorders: 1. Pain 2. Frequency • Treat symptoms with a multimodal approach. • Set realistic goals and expectations as individual responses vary and the evidence base is weak. Controversies in Therapy

• Lack of placebo controlled trials for therapeutic options. • Uncertainty about the mechanism for disease, different therapies target different proposed factors. • Inconsistent responses to therapy among patients, no single treatment found to be universally effective. • Often involves multimodal therapy. Therapy

• Diet • Behavior Modification • Physical Therapy • Oral Medications • Instillation therapy • Surgical treatment Dietary modifications

• Often certain foods exacerbate symptoms – Examples:Tomatoes, pizza, spicy foods, coffee, acidic juices, carbonated beverages, alcohol and chocolate • Anti-inflammatory diet restricts: – Alcohol, citrus, carbonated beverages, coffee, pineapple, berries, tea, tomatoes, vinegar, cheeses, chocolate, aspartame and saccharin, onions, pepper – 64 oz of water should be drank daily • Calcium glycerophosphate (Prelief) may be beneficial in prevention of food related symptoms as is sodium bicarbonate (baking soda). Bassaly et al. Female Pelvic Med Reconstruct Surg 2011 www.ic-network.com/diet Shorter et al. J Urol 2007 Behavioral therapy

• Bladder training may improve urinary frequency and urgency in patients with IC/BPS. • Chaiken et al.1993: – Increases in intervoiding interval and mean number of voids per day in patients with IC/BPS after 12 treatments • Timed voiding protocol/Bladder retraining -Parsons et al. 1991: 50% decrease in symptoms • Behavior modification includes stress reduction, development of coping mechanisms, problem solving, sex therapy, avoid exacerbating activities, psychosocial support. Physical therapy

• High tone pelvic floor dysfunction common in patients with IC/BPS. • Low risk modality. • Holzberg et al. 2001: – Transvaginal Thiele massage, 6 sessions – 9/10 patients had improvements in frequency, nocturia, urgency and pain • Lukban et al. 2001: – Manual physical therapy on 16 patients with IC and pelvic floor dysfunction, 9 visits – 94% improvement in dyspareunia and O’Leary Sant scores Pharmacologic therapy

• Repair epithelial dysfunction. • Modulate neural activity. • Stabilize mast cells.

Hanno P et al. Neuro Urodynam 2010 Oral Medications

• Pentosan polysulfate sodium (Elmiron)

• Hydroxyzine and Cimetidine

• Amitriptyline (TCAs)

• Others: gabapentin, antibiotics, urinary anesthetics, muscle relaxants and narcotics

Moldwin et al. J Urol 2007; Hanno P et al. Neuro Urodynam 2010 Intravesical Therapies

• Intravesical heparin • Clinicians often add – Can be combined with lidocaine, sodium alkalinized lidocaine. bicarbonate, steroids (triamcinolone), Elmiron, gentamicin, and • 50% dimethysulfoxide oxybutynin to “IC (DMSO): FDA approved cocktails”. – Lower concentrations • Cochrane review: available. evidence limited. • May teach patients to do • My cocktail: Kenalog; 1% themselves and allow for lidocaine, Heparin, 0.9% rescue therapy. sodium chloride

Dawson & Jamison Cochrane Database of Systematic Reviews 2007 Sacral neuromodulation (Interstim)

• Currently FDA approved for Urge , Urgency/Frequency, and • Implanted lead along sacral nerve in S3 foramen. • Neuromodulation is based on the induction of somatic afferent inhibition of sensory processing in the spinal cord. • Poor long term outcomes, but potential benefit for urinary symptoms and pain.

Yoost et al Pediatr Adolesc Gynecol 2011; Elhilali et al. Urol 2005 Botox

• Botulinum toxin A • BTX-A has an anti- nociceptive effect on visceral afferent pathways • Ramsay et al (2007): significant symptom relief for at least 10-14 weeks Surgery

• Hydrodistension most • Bladder augmentation common procedure. or cystectomy with – Therapeutic and still urinary diversion. regarded as • Symptom relief not a Diagnostic. guaranteed as pain • Bladder wall resection can persist even after or laser fulguration of cystectomy. ulcers. • Steroid bladder injections.

Kelada & Jones Arch Gynecol Obstet 2007 Abrams et al. Incontinence. Paris Health Publication LTD 2009 Abrams et al. Incontinence. Paris Health Publication LTD 2009 Counseling Patients

• Educate patients about normal bladder function, what is known and not known about IC/BPS, benefits and risk of available treatments, the fact no single treatment has been found effective for the majority of patients and the fact that acceptable symptom control may require trials of multiple therapeutic options before it is achieved.

Hanno HM et al. J Urol 2011 Conclusion

• Interstitial cystitis remains one of the most challenging conditions for providers. – Frustrating due to lack of diagnostic criteria, lack of gold standard test and poor data on therapy. • Prevalence may be higher than current estimates. • Must remember to ask about urgency, frequency as patients often dismiss these symptoms. • Diagnosis and therapy may involve several tests and multimodal treatments. • Involve the patient in therapy as part of team! Helpful Links

• www.AveraUrogyn.org • www.painful-bladder.org • www.ic-network.com • www.nva.org • www.auanet.org