1. Overview of Interstitial Cystitis for the Primary Care Physician WVU WOMENS HEALTH CURRICULUM – Revisions 9/2008 Stanley Zaslau, MD, MBA, FACS Program Director & Associate Professor Section of Urology West Virginia University

2. Objectives In this lecture, participants will learn: –Incidence, epidemiology and pathogenesis of Interstitial Cystitis (IC) Understand the role of the urothelium in the prevention and treatment of IC. –Key concepts in the physical examination of the IC patient –Understand the concept of multimodal therapy for the treatment of IC.

3. Objectives In this lecture, participants will learn: –Key treatments of IC Antidepressants Gabapentin Intravesical therapy Pentosan polysulfate Neuromodulation –Sexual dysfunction in the IC patient – pathogenesis and treatment strategies

4. Introduction Challenge to diagnose “Traditional” view recognizes patients with end-stage disease A continuum--rather than a “fixed” disease Confused with other GU or GYN disorders

5. Definition First reported in 1915 NIH criteria established in 1987 –characterize IC syndrome patient –describe advanced disease –do not define IC –criteria represent a small part of the IC population

6. Definition C. Lowell Parsons, MD The triad of urinary urgency, frequency, and bladder or pelvic pain in the absence of bacterial infection or other definable pathology is the definition of interstitial cystitis Grannum Sant, MD Interstitial Cystitis (IC) Interstitial cystitis is urgency, frequency, and pain in the absence of a defined etiology

7. “Better” Definitions Clinical syndrome Gradually progressive Time line concept: –20’s: mild, intermittent urgency with UTI –30’s: urethral syndrome (persistent -Cx) –40’s: meets NIH criteria for IC –60’s: severe, constant symptoms c/w IC

8. PelvicPainUrgencyFrequency ± Incontinence Clinical Picture of IC Urgency, frequency, nocturia, chronic pelvic pain (CPP) Pain associated with sexual intimacy +/- incontinence Negative culture and sensitivity 1. Parsons CL.

9. Epidemiology Affects 2.5 million women in US Significant number of men affected Studies: –Finnish: incidence 1.2 cases/100,000 people prevalence of 10-11/100,000 –Held: 44,000 cases in US; prevalence of 450,000 cases –May only reflect end-stage disease

10. Epidemiology More recent studies –284 UCSD Female MS attending lectures –All filled out PUF questionnaire 8 items symptom, bother and total score –pelvic pain –urgency –frequency –24% had scores > 10 Parsons, et al Urol 2002

11. Increasingly a Concern in Women Estimated prevalence of self-reported IC in women is 1.5 million 1 IC is often misdiagnosed or underdiagnosed –38% of women scheduled for laparoscopy for suspected endometriosis were cystoscopically confirmed to have IC 2 IC may be a common cause of Chronic Pelvic Pain (CPP) –80% to 85% of women with CPP of unidentified etiology shown to have pain of bladder origin 3 1.Curhan GC et al. J Urol. 1999;161:549-552. 2.Clemons JL et al. 2002;100:337-341. 3.Parsons CL et al. Obstet Gynecol. 2001;98:127-132.

12. ConsiderIC Possible PresentationsFailedEndometriosisTherapy Nonbacterial Prostatitis Recurrent UTI Symptoms Overactive Bladder Treatment Failures Urgency Urgency Frequency Frequency Pain Pain – Dyspareunia – Dyspareunia Refractory PatientsNew Patients 1. Parsons CL et al. Female Patient. May 2002(suppl):12-17. 2. Chung MK et al. JSLS. 2002;6:311-314. 3. Miller JL et al. Urology. 1995;45:587-590.

13. Diagnostic considerations for the Primary Care Physician For patients with: –urgency –frequency –dysuria –painful with sexual intercourse –negative urine cultures and urine cytologies SUSPECT INTERSITIAL CYSTITIS

14. Physical Examination Females –anterior vaginal wall tenderness –suprapubic tenderness –pelvic floor dysfunction Males –suprapubic tenderness –sphincter spasm –tender rectal examination

15. IC Evaluation Tools for the Primary Care Physician Routine testing for the PCP –urine analysis –urine culture –urine cytology –voiding diary Additional testing to be undertaken by the urologist –cystourethroscopy and urodynamics –KCL testing

16. Voids per day Statistics (mean) –Normal population: 6.5times/day –IC population: 16.5 times/day

17. Anesthetic Bladder Capacity Normal people: 1100 cc IC patients: 575 cc

18. Clinical Approach to IC: A Primer for the Primary Care Physician Female History –ICSI –PUF Physical exam Urinalysis and/or culture Elective tests –Potassium sensitivity test –Cystoscopy and hydrodistention –Cystometrogram –Urine for cytology Male History –ICSI –CPSI –PUF Physical exam Urinalysis and/or culture Elective tests –PPMT –Potassium sensitivity test –Cystoscopy and hydrodistention –Cystometrogram –Urine for cytology ICSI = Interstitial Cystitis Symptom Index. PUF = Pelvic Pain and Post-Prostate Massage Test. 1.

19. Pathogenesis Vascular insufficiency Epithelial leak Role of Urinary Potassium Neural Up-regulation Mast Cells

20. Epithelial Leak Leak --> impaired migration of solutes across epithelium “Leak assay” studies (75% + in IC) Potassium sensitivity test + in 90% –suggest leaky epithelium –may suggest neurological inflammatory component

21. Role of Urinary Potassium Principle toxic substance in urine is potassium Toxic to human cells Urine concentration 75 mEq/L Levels > 15 mEq/L depolarize sensory nerves and muscle

22. Role of Urinary Potassium Effects of excessive K+ back diffusion: –vascular destruction –lymphatic destruction –sensory nerve & muscle depolarization –up-regulation of mast cells –induction of substance P and up-regulation of pain fibers –disease progression

23. Potassium Sensitivity May Be a Good Predictor of IC Detects abnormal bladder epithelial permeability Positive in 70% to 90% of IC patients 81% of gynecologic patients with pelvic pain had increased potassium sensitivity 1.Parsons CL et al. J :1054-1057.

24. Role of Urinary Potassium Sodium chloride instillation does not cause symptoms Conclusion: –individual potassium sensitivity: useful diagnostic tool for IC useful even in patients with mild symptoms useful when one is unsure of the diagnosis

25. Neural Up-regulation Up-regulation of sensory nerves in the bladder Seen in severe forms of IC Difficult to treat Can persist after treatment of epithelial defect

26. Mast Cells Role not fully understood Present in IC and non-IC bladders Causative or secondary role in IC? –Cause: degranulate & produce symptoms –Secondary: response to epithelial leak Interact with sensory nerves & release neurotransmitters that activate pain

27. Glycosaminoglycan (GAG) Layer in IC GAG, a mucoprotein, is a component of bladder epithelium GAG may be essential for bladder protection –Irritants and toxins in urine –Bacterial adherence GAG deficiency may result in pathologic changes associated with IC –Permeability of urothelium –Inflammatory/allergic response Lilly JD, Parsons CL.;171:493-496.

28. Vicious Cycle of IC Potassium Leak into Interstitium Bladder Insult Epithelial Layer Dysfunction More Injury Mast Cell Activation and Histamine Release Activation of C-fibers and Release of Substance P Release of Substance P

29. Principles of Treatment--Multimodal Dietary guidelines Stabilize the urothelium –pentosan polysulfate Modulate neural activity –Tricyclic antidepressants like amitriptyline, gabapentin Stabilize mast cells –Antihistamines, ex. Hydroxyzine Stabilize the pelvic floor –sacral neuromodulation

30. Pentosan Polysulfate Mechanism: re-establish GAG layer function and decrease K+ leak The only FDA-approved oral therapy proven effective for IC pain or discomfort Reduces painful symptoms long-term Dose: 100 mg TID (200 mg BID) Full effect takes up to 6 months Side effects: headache, GI upset, hair loss

31. Antihistamines Role: blockade of mast cell release of histamine Dose: 25 mg to 75 mg qHS Useful: –allergy sufferers (spring/fall) Adverse: sedative properties

32. Antidepressants Role: decrease neural pain, decrease urgency and frequency (Ach effect) Dose: 25 mg to 100 mg qHS amitriptyline Some patients respond to lower doses (10 mg) SSRI can also be considered (watch for drug-induced FSD

33. Gabapentin Role: inhibit neural up-regulation and neurogenic spinal cord inflammation Use: chronic unrelenting pain Dose: 300 mg to 2400 mg/day Side effects: sedation Advise: careful dose titration to balance sedative properties

34. Intravesical Agents Dimethyl Sulfoxide (DMSO) –Principle FDA approved intravesical agent –Instilled once weekly for at least 6 weeks –Cocktails: DMSO, sodium bicarbonate, heparin, triamcinolone, bupivicaine –50% objective response rate

35. Sacral Neuromodulation Rationale –Disrupt afferent inputs to the bladder and pelvic floor that cause pathologic voiding –Specifically help regulate capsaicin-sensitive C-afferent neurons –originate from sacral parasympathetic plexus –may relieve pelvic pain/muscle spasm neural input through the pelvic nerve –may aid in detrusor contraction

36. Sacral Neuromodulation Goals of sacral neuromodulation Therapy –Improve pelvic pain –Improve urinary frequency –Improve voided volumes –Improve overall symptom scores IC Symptom Index Chronic Prostatitis Symptom Index

37. Sacral Neuromodulation Potential uses of sacral neuromodulation –Refractory urinary urge incontinence –Non-obstructive urinary retention –Refractory urinary urgency and frequency Interstitial Cystitis

38. Sacral Neuromodulation Current Literature Refractory Urgency/Frequency (IC) Comiter C. –25 patients, prospective study –Mean age 47 years –Trial of sacral nerve stimulation 50% improvement in frequency 50% improvement in nocturia 50% improvement in voided volume 50% improvement in pain –17/25 qualified for permanent implant

39. Sacral Neuromodulation Current Literature Prospective study for refractory IC –Mean follow up: 14 months –Parameters: Daytime frequency: 17 ---> 8.7 voids (p<0.01) Nocturia: 4.5 ---> 1.1 voids (p<0.01) Mean Voided Volume: 111 cc ---> 264 cc (p<0.01) Pain (1-10 scale): 5.8/10 to 1.6/10 (p<0.01) IC Symptom Index: 16.5 ---> 6.8 (p<0.01)

40. Sacral Neuromodulation Current Literature Prospective study for refractory IC –16/17 (94%) had improvement in all parameters at last follow up Conclusions –Sacral neuromodulation is safe and effective treatment of dysfunctional voiding/pelvic pain –Useful treatment for refractory IC symptoms Comiter CV. J Urol 2003 Apr;169(4):1369-73.

41. Sacral Neuromodulation Current Literature West Virginia University Hospital Experience –Collaborative model (Pain Treatment Center and Urology) –All patients evaluated with cystoscopy and urodynamics prior to test stimulation –2 stage approach (test stimulation -> permanent implant

42. Sacral Neuromodulation Current Literature West Virginia University Hospital Experience –To date: 210 test stimulations 195 permanent implants –80 implants have refractory urgency/frequency (IC) Mean age 51 years Mean follow up is 2 year (longest out is 3 years) All with improvement in symptoms and voided volume as well as decline in pelvic pain/bladder spasm Zaslau S, et al. West Virginia Medical Journal, August, 2003

43. Sexual Problems Affecting the IC Patient Pain associated with intercourse –Entry dyspareunia –Deep dyspareunia

44. Entry Dyspareunia “Pain at the opening” –Atrophic vaginitis post menopausal women estrogen loss Tx: topical or oral estrogen replacement –Vaginitis infectious (fungal) Tx: oral or topical antifungal agents

45. Entry Dyspareunia Herpes vulvitis –must rule out other causes first! Vulvodynia –vulvar pain of unknown cause –“feels like dragging sandpaper thru open wound” Infectious vulvitis –glandular enlargement; tx: antibiotics

46. Deep Dyspareunia Most common type of dyspareunia in IC Sources of pain: –Vaginal infections –Vaginal dryness estrogen loss psychological stress

47. Deep Dyspareunia –Bladder pain pain in front portion of vagina caused by penile pressure on bladder trigone –Pain from other pelvic abnormalities endometriosis ovarian diseases pelvic infections diverticulosis

48. Deep Dyspareunia –Pain from pelvic floor muscles most common source of pain for IC patient pelvic floor spasm occurs in 70% of IC patients can prevent penile insertion

49. Vicious cycle of muscle spasm 1. SPASM OF PELVIC MUSCLES 2. FEAR OF PAIN WITH PENETRATION PENILE PENETRATION 3. MORE MUSCLE TIGHTENING 4. PENIS PENETRATES INTO SPASTIC, TENDER MUSCLES 5. FURTHER TIGHTENING OF MUSCLES

50. IC and Female Sexual Dysfunction (FSD) 100 patients with IC FSFI administered –Assess 6 domains of sexual function Desire Arousal Orgasm Lubrication Satisfaction Pain

51. IC and FSD Results: –Mean age 39 years –Impairment in all domains “50-75% of the time” Conclusions –FSD in IC involves more than pelvic pain Zaslau, S et al FSFF, Vancouver, BC 2002

52. FSD in IC: 1st 400 Patients 400 IC patients FSFI administered on line at IC-Network Compared to two groups –Controls (131) –Female sexual arousal disorder (129)

53. FSD in IC 1st 400 Patients Results –Statistically significant decrease in all domains when compared to controls –Stastically significant decrease in all domains when compared to Arousal Disorder Group –Lowest scores: pain Zaslau, et al AUA 2003, Chicago, IL.

54. Conclusions: IC and FSD Global sexual dysfunction affecting all domains May be age related and progressive Pain domain has lowest scores Treatment is multimodal and may involve counseling, sex therapy and physical therapy

55. General Treatment Principles Talk to your partner –create “game plan” to deal with partner needs –role for physician, social worker, sex therapist Don’t focus only on penetration –Shift major focus to foreplay, full body massage, deep kissing, fondling, oral-genital contact

56. General Treatment Principles Watch out for medication effects on orgasm –medications can cause fatigue and/or loss of sexual desire –antidepressants impair orgasm Go slow –forget the terrible memories –Relax to prevent pelvic muscle spasm –Go slow with insertion and thrusting

57. General Treatment Principles Lots of lubrication –aids in penetration –especially helpful in vulvodynia Be in control –goes along with going slow –let the patient call the shots –communicate!

58. General Treatment Principles Find the right position –There is no “perfect position” –Goal: minimize vaginal tenderness, adjust vault-penis angle and partner weight –Missionary: most discomfort for female partner (penile-->bladder base pressure) –Female superior: more control for IC female

59. General Treatment Principles Go one step at a time –Step-wise approach for vaginal penetration –First goal: NOT penis in vagina = orgasm! –Don’t focus on vaginal entry initially –Instead: superficial penetration and maximize foreplay

60. General Treatment Principles Avoid intercourse during flares –Flare can be related to menses –Increased urinary frequency and pelvic pain = flare –Focus away from intercourse and onto foreplay! Take advantage of remissions –take things slow; “roll with the punches”

61. General Treatment Principles Take a warm bath after sex –can relax pelvic floor muscles –can be therapeutic after sex –however, warmth can be irritating! Avoid urinary tract infections –void before and after sexual relations Avoid use of diaphragm –can increase UTI and pelvic pain/irritation

62. General Treatment Principles Use vaginal dilators/biofeedback –can relax vaginal vault –patient in total control of insertion –step-wise treatment strategy –minimizes anxiety

63. General Treatment Principles Read and learn more about IC –Interstitial Cystitis Association (www.ichelp.org) –Interstitial Cystitis Network (www.ic-network.com)

64. Summary Interrelationships between conditions: –Overactive Bladder No bacteriuria No bladder pain –Urinary Tract Infection Bacteriuria and bladder pain –Interstitial Cystitis Bladder pain and no bacteriuria

65. Summary (continued) The prevalence of IC is much higher than previously estimated IC should be considered in patients who have failed standard therapy for endometriosis (prior to hysterectomy), OAB, or have symptoms of recurrent/chronic UTI and do not improve on antibiotics Increase awareness of IC as part of CPPS differential diagnosis Symptoms of CP/CPPS appear to be similar to IC Treatment of IC is multimodal (pentosan polysulfate, antidepressants, antihistamines, role for sacral neuromodulation in treatment failures) *NBP = non-bacterial

66. References – 1 Peters KM, Killinger KA, Carrico DJ, Ibrahim IA, Diokno AC, and Graziottin A: Sexual Function and Sexual Distress in Women with Interstitial Cystitis: A Case Control Study. Urology. 2007; 70(3): 543-547. Zaslau S, Triggs J, Morgan L, Osborne J, Subit M, Riggs D: “Characterization of Female Sexual Dysfunction in Patients with Interstitial Cystitis.” Presented at the American Urological Society Meeting, Chicago, IL, April 27, 2003.

67. References - 2 Zaslau S, Subit MJ, Mohseni HF, Riggs D, Jackson B, Kandzari S: “Sexual Dysfunction in Patients with Interstitial Cystitis.” Presented at the American Urogynecology Meeting, Hollywood, FL, September 12, 2003. Zaslau S, Subit MJ, Mohseni HF, Riggs D, Jackson B, Kandzari S. “Sexual Dysfunction in Patients with Interstitial Cystitis: Initial Analysis of Under 40 Cohort.” Presented at the Mid-Atlantic Section of the American Urological Society Meeting, Boca Raton, FL, October 26- 29, 2003.

68. References - 3 Zaslau S: Blueprints in Urology, 1st ed. Boston, MA: Blackwell Science, Inc., 2004. Zaslau S: SOAP Notes in Urology, 1st ed. Baltimore, MD: Lippincott Williams and Wilkins, Inc., 2006. Messing EM. Interstitial cystitis and related syndromes. In: Campbell’s Urology, 6th Edition. Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (eds). Philadelphia: WB Saunders Co., Volume 1, Chapter 24, pp. 982-1005, 1992.