Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders

1. Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders Roc McCarthy, D.O.

2. Painful Bladder Syndrome Painful bladder syndrome/interstitial cystitis (PBS/IC) is a condition diagnosed on a clinical basis and requiring a high index of suspicion by the clinician. Simply put, it should be considered in the differential diagnosis of the patient who presents with chronic pelvic painthat is often exacerbated by bladder filling and associated with urinary frequency. The term Interstitial cystitis, was not at all descriptive of the clinical syndrome or the pathologic findings in many cases leading to the current effort to reconsider the name of the disorder and even the way it is positioned in the medical spectrum

3. Overview PBS/IC encompasses a major portion of the "painful bladder" disease complex -including bladder and/or urethral and/or pelvic pain, irritative voiding symptoms (urgency, frequency, nocturia, dysuria), and sterile urine Painful bladder conditions with well-established causes include: - radiation cystitis - cystitis caused by microorganisms that are not detected by routine culture methodologies - systemic disorders that affect the bladder - gynecologic disorders

4. Overview Symptoms are mostly allodynic, an exaggeration of normal sensations There are no pathognomonic findings on pathologic examination Petechial hemorrhages after hydrodistention is no longer considered the sine qua non of PBS/IC PBS/IC is truly a diagnosis of exclusion. It may have multiple causes and represent a final common reaction of the bladder to different types of insults.

5. HISTORICAL PERSPECTIVE IC was recognized as a pathologic entity during the 19th century Joseph Parrish, a Philadelphia surgeon, described three cases of severe lower urinary tract symptoms in the absence of a bladder stone in an 1836 text and termed the disorder "tic doloureux of the bladder." 1887 Skene used the term interstitial cystitis to describe an inflammation that has "destroyed the mucous membrane partly or wholly and extended to the muscular parietes.“ Early 20th century, Guy Hunner reported on eight women with a history of suprapubic pain, frequency, nocturia, and urgency lasting an average of 17 years . They had red, bleeding areas…….."Hunner's ulcer." 1949 Hand reported 223 cases "I have frequently observed that what appeared to be a normal mucosa before and during the first bladder distention showed typical interstitial cystitis on subsequent distention." He notes, "small, discrete, submucosal hemorrhages, showing variations in form, and dot-like bleeding points” 1978 Walsh coined the term glomerulations to describe the petechial hemorrhages that Hand had described 1978 Stamey discussed the "early diagnosis" of IC that attention turned from looking for an ulcer to make the diagnosis to the concepts that (1) symptoms and glomerulations at the time of bladder distention under anesthesia were the disease hallmarks and (2) the diagnosis was primarily one of exclusion Dr. Vicki Ratner, an orthopedic surgery resident in New York City, who founded the first patient advocacy group, the Interstitial Cystitis Association, in the living room of her New York City apartment in 1984

6. DEFINITION Interstitial cystitis (IC) - clinical diagnosis primarily based on symptoms of urgency/frequency and pain in the bladder and/or pelvis. - The International Continence Society (ICS) prefers the term painful bladder syndrome (PBS), defined as "the 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 infection of other obvious pathology” The ICS reserves the diagnosis of IC for patients with "typical cystoscopic and histological features," without further specifying these. In the absence of clear criteria for "IC," this chapter will refer to PBS/IC and IC interchangeably

7. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diagnostic Criteria for Interstitial Cystitis To be diagnosed with interstitial cystitis, patients must have either glomerulations or a classic Hunner ulcer, and they must have either pain associated with the bladder or urinary urgency. An examination for glomerulations should be undertaken after distention of the bladder under anesthesia to 80 to 100 cm H2O for 1 to 2 minutes. The bladder may be distended up to two times before evaluation. The glomerulations must be diffuse-present in at least three quadrants of the bladder-and there must be at least 10 glomerulations per quadrant. The presence of any one of the following excludes a diagnosis of interstitial cystitis: 1. Bladder capacity of greater than 350 mL on awake cystometry using either a gas or liquid filling medium 2. Absence of an intense urge to void with the bladder filled to 100 mL of gas or 150 mL of liquid filling medium 3. The demonstration of phasic involuntary bladder contractions on cystometry using the fill rate just described 4. Duration of symptoms less than 9 months 5. Absence of nocturia 6. Symptoms relieved by antimicrobial agents, urinary antiseptic agents, anticholinergic agents, or antispasmodics 7. A frequency of urination while awake of less than 8 times per day 8. A diagnosis of bacterial cystitis or prostatitis within a 3-month period 9. Bladder or ureteral calculi 10. Active genital herpes 15. Uterine, cervical, vaginal, or urethral cancer 11. Urethral diverticulum 16. Cyclophosphamide or any type of chemical cystitis 12. Tuberculous cystitis 17. Radiation cystitis 13. Benign or malignant bladder tumors 18. Vaginitis 14. Age younger than 18 years Roc suggested adding mom with IC

8. DEFINITION Recent international consultations have essentially agreed that the nomenclature of "interstitial cystitis" be revised to "painful bladder syndrome/interstitial cystitis.“ This recognizes that it is the symptoms that drive treatment, and the question as to whether IC refers to a distinct subgroup of the painful bladder syndrome is, as yet, unclear. For purposes of PBS/IC, the symptom of pain should be broadened to include "pressure" and "discomfort."

9. Interstitial Cystitis Database (ICDB) Study Eligibility Criteria 1. Providing informed consent to participate in the study. 2. Willing to undergo a cystoscopy under general or regional anesthesia when indicated, during the course of the study. 3. At least 18 years of age. 4. Having symptoms of urinary urgency, frequency, or pain for more than 6 months. 5. Urinating at least 7 times per day, or having some urgency or pain (measured on linear analog scales). 6. No history of current genitorurinary tuberculosis. 7. No history of urethral cancer. 8. No history of bladder malignancy, high-grade dysplasia, or carcinoma in situ 9. Males: no history of prostate cancer. 10. Females: no occurrence of ovarian, vaginal, or cervical cancer in the previous 3 years 11. Females: no current vaginitis, clue cell, trichomonas, or yeast infections. 12. No bacterial cystitis in the previous 3 months. 13. No active herpes in the previous 3 months. 14. No antimicrobials for urinary tract infections in previous 3 months. 15. Never having been treated with cyclophosphamide. 16. No radiation cystitis. 17. No neurogenic bladder dysfunction (e.g., due to a spinal cord injury, stroke, Parkinson's disease, multiple sclerosis, spina bifida, or diabetic cystopathy). 18. No bladder outlet obstruction (determined by urodynamic investigation). 19. Males: no bacterial prostatitis for previous 6 months. 20. Absence of bladder, ureteral, or urethral calculi for previous 3 months. 21. No urethritis for previous 3 months. 22. Not having had a urethral dilation, cystometrogram, bladder cystoscopy under full anesthesia, or a bladder biopsy in previous 3 months. 23. Never having had an augmentation cystoplasty, cystectomy, cystolysis, or neuroectomy. 24. Not having a urethral stricture of less than 12 French.

10. EPIDEMIOLOGY Epidemiology studies are hampered by many problems. - Lack of an accepted definition - Absence of a validated diagnostic marker - Questions regarding etiology and pathophysiology make much of the literature difficult to interpret - Most apparent when one looks at the variation in prevalence reports in the United States 20,000 per 100,000 women vs. 1.2 per 100,000 population in Japan

11. EPIDEMIOLOGY It has been estimated that the prevalence of chronic pain due to benign causes in the population is at least 10% A childhood presentation is extremely rare and must be differentiated from the much more common and benign-behaving extraordinary urinary frequency syndrome of childhood

12. EPIDEMIOLOGY Held et al, 1990- Surveyed: (1) randomly 127 board-certified urologists, (2) 64 IC patients selected by the surveyed urologists and divided between the last patient with IC seen and the last patient with IC diagnosed, (3) 904 female patients belonging to the Interstitial Cystitis Association, and (4) a random phone survey of 119 persons from the U.S. population. This study reached the following conclusions: 1. There were 43,500 to 90,000 diagnosed cases of IC in the United States (twice the Finnish prevalence). 2. Up to a fivefold increase in IC prevalence occurred if all patients with painful bladder and sterile urine had been given the diagnosis, yielding up to a half million possible cases in the United States. 3. Median age at onset is 40 years. 4. Late deterioration in symptoms is unusual. 5. There is a 50% temporary spontaneous remission rate, with a mean duration of 8 months. 6. The incidence of childhood bladder problems is 10 times higher in IC patients versus controls. 7. The incidence of a history of urinary tract infection is twice that of controls. 8. Fourteen percent of IC patients were Jewish versus 3% who were Jewish in a general population sample. 9. IC patients have a lower quality of life than dialysis patients. 10. Costs including lost economic production, in 1987, were $427 million.

13. EPIDEMIOLOGY Prevalence estimates per 100,000 persons United States: 15-24,000 Netherlands: 7 Finland: 10.6-450 Japan: 1.2 Female to male ratio = 5:1

14. Associated Diseases No reports have ever documented a relationship to suggest that IC is a premalignant lesion. Allergies Focal vulvitis/vulvar Vestibulitis Sjögren's syndrome IBS Fibromyalgia Lupus IBD

15. ETIOLOGY It is likely that PBS/IC has a multifactorial etiology that may act predominantly through one or more pathways resulting in the typical symptom-complex feline urologic syndrome

16. Infection Diagnosis of PBS/IC is made only after a patient has been seen by a number of physicians and treated with antibiotics for presumed urinary tract infection without resolution of symptoms The symptom-complex looks to the patient and physician like an infectious process Not just urine but bladder epithelium as well must be cultured for appropriate microorganisms, including bacteria, viruses, and fungi The role of infection in the pathogenesis of IC remains a mystery. At this time there are little data to support the role of an infectious etiology but investigators keep returning to an infectious theory. "It is logical to suggest that even if organisms are not causative agents, their presence may lead to immune and host-cell responses that could initiate or exacerbate an inflammatory state."

17. Autoimmunity/Inflammation Immune/neuroimmune mechanisms may have an important role in the pathogenesis of PBS/IC. -Excessive release of sensory nerve neurotransmitters and mast cell inflammatory mediators is thought to be responsible for the development and propagation of symptoms Can IC may represent some type of autoimmune disorder? Three different possibilities exist: (1) IC is caused by a direct autoimmune attack on the bladder (2) Some of the autoimmune symptoms and pathology of IC arise indirectly as a result of tissue destruction and inflammation from other causes (3) Autoimmune phenomena in IC patients are coincident and unrelated to the disease No clear indication of a primary role for autoimmunity as the cause of IC has been observed

18. Mast Cell Involvement Mast cells have frequently been reported to be associated with IC, both as a pathogenetic mechanism and as a pathognomonic marker Mast cells are strategically localized in the urinary bladder close to blood vessels, lymphatics, nerves and detrusor smooth muscle. Studies strongly suggest that IC is a syndrome with neural, immune, and endocrine components in which activated mast cells play a central, although not primary, pathogenetic role in many patients

19. Bladder GAG Layer/Epithelial Permeability Parsons hypothesized that IC is the result of some defect in the epithelial permeability barrier of the bladder surface glycosaminoglycans Major classes of glycosaminoglycans (GAGs) include hyaluronic acid, heparin sulfate, heparin, chondroitin 4-sulfate and chondroitin 6-sulfate, dermatan sulfate, and keratan sulfate Does seems that there is a population of IC patients with increased epithelial permeability. Treatments that tend to damaged GAG layer, including transurethral resection and laser of ulcerated areas, bladder distention, silver nitrate administration, and use of the organic solvent DMSO have all been used with varying results to treat IC. Conclusion: Increased permeability and epithelial dysfunction must be only a part of the story.

20. Neurobiology Inflammatory painful stimuli, especially if repeated, can chronically alter innervation, central pain-processing mechanisms, and tissue responses Numerous studies indicate increased sympathetic activity in IC Important to note that the nervous system itself almost surely contributes to the chronic nature of this pain syndrome, regardless of initiating etiology Non-nociceptive Pain: Characteristic Clinical Features 1. The description of the pain seems inappropriate in comparison with the degree of tissue pathology, or no tissue pathology may be discernible. 2. Noxious stimuli result in a pain experience that is greater and more unpleasant than would normally be expected (hyperalgesia). 3. Normally non-noxious stimuli may result in pain (allodynia). 4. The extent of the pain boundary is greater than would be expected on the basis of the site of the original tissue pathology.

21. Urine Abnormalities Antiproliferative Factor (APF)- The finding that cells from the bladder lining of normal controls grow significantly more rapidly in culture than cells from IC patients led to the discovery of an (APF) produced by the urothelium of IC patients. It is 8 protein produced by bladder uroepithelial cells of PBS/IC patients. Inhibits bladder cell proliferation Is a sensitive and specific biomarker for IC. It may ultimately unlock the etiology of the syndrome and could provide avenues for development of future therapies.

22. Other Potential Causes Pelvic floor dysfunction Obstruction of lymphatics or vascular structures Hormonal

23. PATHOLOGY Knifelike Hunner's ulcer in interstitial cystitis. Nonulcerative form of interstitial cystitis with dense lymphoid infiltrate in the lamina propria One can have pathology consistent with the diagnosis of IC, but there is no microscopic picture pathognomonic of this syndrome. The role of histopathology in the diagnosis of IC is primarily one of excluding other possible diagnoses

24. DIAGNOSIS Considered one/part of the chronic visceral pain syndromes, affecting the urogenital and rectal area, well described but poorly understood (Including vulvodynia, orchialgia, penile pain, perineal pain, and rectal pain) Various gynecologic problems can mimic the pain of IC Laparoscopy should not be considered a part of any routine evaluation of PBS/IC unless a gynecologist believes it is likely to benefit the patient. Presumptive diagnosis can be made merely by ruling out known causes of frequency and pain/urgency in a patient with compatible chronic symptoms (Complete H&P, cultures, and cystoscopy) Cystometry in conscious IC patients generally demonstrates normal function, the exception being decreased bladder capacity and hypersensitivity. Pain on bladder filling that reproduces the patient's symptoms is very suggestive of IC

25. Cystoscopy Typical appearance of glomerulations after bladder distention in a patient with nonulcerative interstitial cystitis. Typical appearance of Hunner's ulcer in a patient with interstitial cystitis before bladder distention.

26. Potassium Chloride Test Parsons has championed an intravesical KCl challenge, comparing the sensory nerve provocative ability of sodium versus potassium using a 0.4 M KCl solution. Pain and provocation of symptoms constitutes a positive test. Whether the results indicate abnormal epithelial permeability in the subgroup of positive patients or hyper-sensitivity of the sensory nerves is unclear IF used as a diagnostic test for IC, the KCl test is not valid Is very non-specific Recent study reported a 36% false-positive rate in asymptomatic men Prospective and retrospective studies looking at the KCl test for diagnosis in patients presenting with symptoms of PBS/IC have found no benefit of the test in comparison with standard techniques of diagnosis Is a predictive test for response to IC-specific medications (Elmiron and other heparinoids that work by “coating” the bladder lining)

27. CLINICAL SYMPTOM SCALES There are three published PBS/IC symptom questionnaires: 1) University of Wisconsin IC Scale 2) O'Leary-Sant IC Symptom Index 3) Pelvic Pain and Urgency/Frequency (PUF) Scale.

28. ASSESSING TREATMENT RESULTS Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF) Global Response Assessment (GRA) It has been not only a difficult condition to diagnose but also a difficult condition for which to assess therapeutic impact. In a chronic, devastating condition with primarily subjective symptomatology, no known cause, and no cure, patients are desperate and often seem to respond to any new therapy (at least short term) Placebo effects plus disease natural history of regression can result in high rates of good outcomes, which may be misattributed to specific treatment effects Percentage of patients initially improved

29. CONSERVATIVE THERAPY Patient education and empowerment is an important initial step in therapy There are data that timed voiding and behavioral modification therapy can be helpful in the short-term, especially in patients in whom frequency rather than pain predominates Interstitial Cystitis Association Recommendations of Foods to Avoid: Milk/Dairy ProductsNuts Aged cheeses Sour cream     Alcoholic beverages Yogurt     Carbonated drinks Chocolate CoffeeVegetables Tea   Fruit juices Fava beans   Lima beans Seasonings Onions     Mayonnaise Tofu     Ketchup Soybeans  Mustard Tomatoes     Salsa Fruits Spicy foods  Soy sauce Apples     Miso Apricots     Salad dressing Avocados     Vinegar Bananas   Cantaloupes Preservatives and Additives Citrus Fruits     Benzyl alcohol Cranberries     Citric acid Grapes     MSG Nectarines     Artificial sweeteners Peaches     Pineapples       Food coloring Pomegranates   Rhubarb Strawberries Tobacco Caffeine   Diet pills     Junk foods Rye bread     Recreational drugs Sourdough bread     Allergy medications with ephedrine or pseudoephedrine Meats and Fish Certain vitamins Aged, canned, cured, processed, smoked meats 

30. ORAL THERAPY Tricyclic Antidepressants (Amitriptyline) have three major pharmacologic actions: (1) central and peripheral anticholinergic actions (2) block the active transport system in the presynaptic nerve ending responsible for reuptake of serotonin and noradrenaline (3) they are sedatives Antihistamines- Used since late 1950s, postulated that the local release of histamine may be responsible for, or accompany the development of, IC. Sodium Pentosan Polysulfate- Aheparin analog, thought to decrease the epithelial permeability barrier (GAG layer) - 3% to 6% of which is excreted into the urine from oral pill

31. Miscellaneous Agents Systemic corticosteroids Hormones Vitamin E Anticholinergics Antispasmodics Calcium channel antagonist (nifedipine) Cysteinyl leukotriene D4 receptor antagonist (montelukast) Oral L-arginine, an over-the-counter amino acid preparation, was purported to increase nitric oxide-related enzymes

32. Analgesics The long-term, appropriate use of pain medications forms an integral part of the treatment of a chronic pain condition such as IC With the results of major surgery anything but certain, the use of long-term opioid therapy in the rare patient who has failed all forms of conservative therapy over many years may also be considered

33. INTRAVESICAL AND INTRADETRUSOR THERAPY Intravesical lavage with one of a variety of preparations has remained a mainstay of treatment in the therapeutic armamentarium of IC DrugRandomized Controlled Trial% SuccessSilver nitrate No 60% Clorpactin WCS-90 No 60% Dimethylsulfoxide Yes 70% Bacillus Calmette-Guérin Yes No proven efficacy Resiniferatoxin Yes No proven efficacy Hyaluronic acid Yes No proven efficacy Heparin No 60% Chondroitin sulfate No 33% Lidocaine No 65% Capsaicin No No demonstrated efficacy Oxybutynin No Efficacy suggested Doxorubicin No Anecdotal efficacy Pentosan polysulfate Yes 40%

34. Dimethyl sulfoxide (DMSO) DMSO is a product of the wood pulp industry and a derivative of lignin It has exceptional solvent properties and is freely miscible with water, lipids, and organic agents Pharmacologic properties include membrane penetration, enhanced drug absorption, anti-inflammatory action, analgesic action, collagen dissolution, muscle relaxation, and mast cell histamine release It has been suggested that DMSO actually desensitizes nociceptive pathways in the lower urinary tract Authors administer 50 mL of 50% DMSO as a bladder "cocktail" with 10 mg of triamcinolone 40,000 units of heparin, and 44 mEq of sodium bicarbonate

35. NEUROMODULATION It is reasonable to consider therapeutic options that directly interface with the nervous system in the treatment of PBS/IC. This approach is further supported by the association of pelvic floor dysfunction with pelvic pain syndromes Direct sacral nerve stimulation has been explored in the treatment of IC and urgency/frequency and is referred to as neuromodulation As initially practiced, trial stimulation was performed with a percutaneous temporary electrode for a 3- to 4-day temporary stimulation period to access efficacy The S3 nerve is most frequently used A wire electrode is inserted into the foramen and connected to an external pulse generator If the trial is successful, the patient would be considered for implantation of a permanent neural prosthesis. More recently, a staged procedure has supplanted the traditional percutaneous approach (or in a van down by the river)

36. HYDRODISTENTION Hydrodistention of the bladder under anesthesia Technically a surgical treatment, is often the first therapeutic modality employed Often as a part of the diagnostic evaluation Results vary markedly Our method is to perform an initial cystoscopic examination (which is generally unremarkable), obtain urine for cytology, and distend the bladder for 1 to 2 minutes at a pressure of 80 cm H2O. The bladder is emptied and then refilled to look for glomerulations or ulceration. A therapeutic hydraulic distention follows for another 8 minutes. Biopsy, if indicated, is performed after the second distention Responses in patients with a bladder capacity under anesthesia of less than 600 mL showed 26% with an excellent and 29% with a fair result

37. SURGICAL THERAPY The surgical therapy of IC is an option after all trials of conservative treatment have failed, a point that cannot be overemphasized IC, although a cause of significant morbidity, is a nonmalignant process with a temporary spontaneous remission rate of up to 50% and does not directly result in mortality Many surgical approaches have been employed for IC: Sympathectomy and intraspinal alcohol injections Differential sacral neurotomy Transurethral resection/laser of a Hunner's ulcer Supratrigonal cystectomy Urinary diversion with or without cystourethrectomy is the ultimate surgical answer to the dilemma of IC

38. PRINCIPLES OF MANAGEMENT History/Initial AssessmentThe initial assessment consists of a frequency/volume chart, focused physical examination, urinalysis, and urine culture. Cytology and cystoscopy are recommended if clinically indicated.   Only if findings are unable to explain the symptoms are they diagnosed with PBS/IC. Initial TreatmentPatient education, dietary manipulation, nonprescription analgesics, and pelvic floor relaxation techniques. When these fail, or symptoms are severe and conservative management unlikely to succeed, oral medication or intravesical treatment can be prescribed. Secondary AssessmentIt is reasonable to consider further evaluation (urodynamics, pelvic imaging, and cystoscopy with bladder distention and possible bladder biopsy under anesthesia).

39. PRINCIPLES OF MANAGEMENT Refractory PBS/ICPts. with persistent, unacceptable symptoms despite oral and/or intravesical therapy are candidates for more aggressive modalities (neuromodulation, pain clinic consultation, narcotic analgesia, and/or experimental protocols). The last step in treatment is usually some type of surgical intervention aimed at increasing the functional capacity of the bladder or diverting the urine stream (augmentation). A Philosophy of ManagementI believe that, because of the natural history of the disorder, it is best to cautiously progress through a variety of treatments. One should encourage patients to maximize their activity and live as normal a life as possible, not becoming a prisoner of the condition. Although some activities or foods may aggravate symptoms, nothing has been shown to negatively affect the disease process itself. Therefore, patients should feel free to experiment and judge for themselves how to modify their lifestyle without the guilt that comes from feeling they have harmed themselves if symptoms flare.

40. URETHRAL SYNDROME In 1945, the distinguished American physician Richard Cabot was quoted as having stated that “any pain within two feet of the female urethra for which one cannot find an adequate explanation should be suspected of coming from the female urethra” The urethral syndrome is a very nonspecific constellation of symptoms including urinary frequency, urgency, dysuria, and suprapubic discomfort without any objective findings of urologic abnormality to account for the symptoms The concept of the urethral syndrome, chronic or acute, is now essentially a historical one and no longer alluded to in the modern medical literature

41. The End

42. Thanks