Interstitial Cystitis: Diagnosis and Treatment

INTERSTITIAL CYSTITIS: DIAGNOSIS AND TREATMENT Shawna L. Johnston, MD, FRCSC, I Thomas C. Mainprize, MD, FRCSC 2 IDepartment of Obstetrics and Gynaecology, Queen's University, Kingston ON Department of Obstetrics and Gynecology, University of Calgary, Calgary AB

2

Abstract: Interstitial cystitis is a chronic disease characterized by urinary urgency, voiding frequency, and suprapubic pain, in the presence of sterile and cytologically normal urine. Various diagnostic criteria have been proposed, but the diagnosis of interstitial cystitis is essentially still one of exclusion. Health care providers need to consider the diagnosis of interstitial cystitis in women presenting with irritative voiding complaints or suprapubic pain, and provide appropriate patient education and management options for patients with this disease. The symptoms of interstitial cystitis create substantial psychological, social, and hygienic problems, and diminish the quality of life of the patient and her family. Treatment should address the relief of symptoms, the regeneration of the bladder lining, and the restoration of the quality of life. Pharmacological, surgical, and supportive therapies exist to achieve these objectives and are probably most effective when used in combination.

Resume: La cystite interstitielle est une maladie chronique qui se caracterise par la miction imperieuse et frequente et des douleurs sus-pubiennes, en presence d'une urine sterile et normale au niveau cytologique. On a propose divers criteres de diagnostic, mais il n'en demeure pas moins qu'en definitive, le diagnostic de cystite interstitielle en est un d'exclusion. Lorsqu'une patiente se plaint de mictions douloureuses et de douleurs sus-pubiennes, les fournisseurs de soins de sante doivent envisager la possibilite d'un diagnostic de cystite interstitielle et donner it la patiente !'information dont elle a besoin sur cette affection et sur les options de traitement. Les symptomes accompagnant cette affection sont la source de problemes importants aux niveaux psychosocial, social et hygienique et ils reduisent la qualite de vie de ces patientes et de leur famille. Le traitement doit porter sur le soulagement des symptomes, la regeneration de la membrane interne de la vessie et la restauration de la qualite de vie. Ces objectifs peuvent etre atteints, grace it des traitements pharmacologiques et chirurgicaux et it des therapies de soutien dont I'efficacite est probablement plus grande lorsqu'on les utilise en combinaison.

J Obstet

Gynaecol Can 200 I ;23(9):785-94

KeyWords bladder; bladder diseases; urination disorders; urinary tract disorders, female; cystitis, interstitial; epidemiology; etiology; quality of life; diagnosis; treatment Competing interests: Dr. Mainprize has served on an Alza Canada advisory board. jOGC

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INTRODUCTION

Interstitial cystitis is a chronic disease characterized by urinary urgency, voiding frequency, and suprapubic pain, in the presence of sterile and cytologically normal urine. I It occurs more frequently in women than in men. 2 Though first described almost a century ago by Hunner,3 its etiology remains unclear. Various diagnostic criteria have been proposed, but the diagnosis of interstitial cystitis is essentially still one of exclusion. Because symptoms overlap, interstitial cystitis is often mistaken for overactive bladder, endometriosis, pelvic inflammatory disease (PlO), vulvovaginitis, or acute bacterial cystitis. Health care providers need to consider the diagnosis of interstitial cystitis in women presenting with irritative voiding complaints or suprapubic pain, and provide appropriate patient education and management options for patients with this disease. The following text will provide a comprehensive and current review of interstitial cystitis. METHODS

English language journals indexed in Medline and the Cochrane Review databases were searched for relevant articles addressing the epidemiology, etiology, diagnosis, and treatment of interstitial cystitis. Articles focusing on quality of life issues for patients with interstitial cystitis were also retrieved. Search terms included "bladder diseases," "urination disorders," "urinary tract disorders, female," "cystitis, interstitial," "epidemiology," "etiology," "qualiry oflife," "diagnosis," and "treatment." The references in retrieved articles were reviewed for potentially relevant articles not identified through database searches. EPIDEMIOLOGY

The actual prevalence of interstitial cystitis is difficult to determine. Differences in disease definition and detection contribute to disparate prevalence estimates. Ito et al. 4 reported a prevalence of interstitial cystitis of 4.5 per 100,000 Japanese women, while amongst Finnish women, Oravisto5 reported a prevalence of 18.6 per 100,000 women. In the United States, the prevalence has been reported to b~ as high as 87 per 100,000 women. 6 As yet, there are no good epidemiological data available for the Canadian population. SEPTEMBER 200 I

While interstitial cystitis can occur in both men and women at any age, it seems to occur much more commonly in women. 2 Population-based studies have identified that more than 90 percent of cases occur in women between the ages of 20 and 50 years, with median ages at diagnosis ranging from 43 to 46 years. 2,7,8 Most patients with interstitial cystitis are Caucasian. 8 ,9 Although a specific genetic component has not yet been identified, such a mechanism has been suggested by anecdotal reports of monozygous twin sisters and mother-daughter pairs with confirmed diagnoses of interstitial cystitis. I ETIOLOGY

Many theories have been suggested as possible etiologies for interstitial cystitis, but no one theory to date has been universally accepted (Table 1). It is more likely that interstitial cystitis is a heterogeneous clinical syndrome, with several different factors serving to initiate a common pathogenic process in the bladder. A multifactorial etiology would also account for the difficulties in objectively defining and diagnosing interstitial cystitis. There is no good natural or induced animal model for interstitial cystitis in humans. It may be that interstitial cystitis is an idiopathic auto immune disease. Defects in the permeability of the surface urothelium have been postulated as the cause of the disease. Other research suggests that interstitial cystitis is a neuro-inflammatory disease of the bladder mediated by neuropeptides and mast cells, or the result of underlying chronic infection with fastidious microorganisms. Each of these theories is discussed in detail below. AUTOIMMUNE DISEASE

The suggestion that interstitial cystitis is an autoimmune disease has been largely based on epidemiological observations. Patients with interstitial cystitis are 100 times more likely than the general population to suffer from inflammatory bowel disease and 30 times more likely to have systemic lupus erythematosis. 1O Similar to other auto immune diseases, interstitial cystitis goes through episodes of exacerbation and remission. 10 Serum autoantibodies (including antinuclear antibodies) have been identified in up to 50 percent of patients with interstitial cystitis. I 1 Several of these antibodies are unique to interstitial cystitis, 12, 13and others are shared by auto immune diseases like atopic dermatitis and asthma. 14 Unlike other autoimmune TABLE I PROPOSED ETIOLOGIES FOR INTERSTITIAL CYSTITIS • autoimmune disease • altered urothelial permeability • infection • neuro-inflammatory disease

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diseases, however, immunosuppressive drug therapy does not appear to provide objective benefit to patients with interstitial cystitis. 15 It may be that the immunologic bladder responses seen in interstitial cystitis are secondary, nonspecific responses to bladder tissue damage and inflammation rather than the primary pathogenic mechanism of the disease. ALTERED UROTHELlAL PERMEABILITY

Defects in the surface urothelium of the bladder may be responsible for the development of interstitial cystitis. The surface urothelium is covered and protected by a mucin layer containing long polymeric molecules known as glycosoaminoglycans (GAGs).IG Such molecules are similar in structure to heparin. The GAG layer is strongly hydrophilic, enabling binding of a barrier layer of water against the urothelium. The GAG layer is thus thought to provide a defence against penetration by bacteria, viruses, solutes and metabolites, and antigenic proteins. A qualitative or quantitative defect in the GAG layer-a "leaky epithelium"-has been proposed as the underlying mechanism for disease in interstitial cystitis. IG Toxic components of the urine are able to enter the interstices of the bladder wall, causing inflammation and characteristic symptoms and epithelial changes. Whether or not the leaky urothelium is the primary defect in this condition or a secondary phenomenon due to other etiologic factors remains unanswered. Urinary GAG excretion is elevated in patients with interstitial cystitis as compared to controls, 17perhaps signalling an inability of the bladder wall to retain a viable GAG layer. Parsons et al. 18 demonstrated an increased sensitivity to intravesical potassium in interstitial cystitis patients as compared to controls, and a similar heightened pain response to potassium in normal subjects after temporary bladder mucus injury with protamine. INFECTION

Interstitial cystitis is, by definition, a disease in which the urine is sterile. Some investigators, however, have suggested that chronic infection with fastidious or cryptic bacteria may be the cause of interstitial cystitis. 19 Such organisms are not detected by standard culture, and their presence may only be uncovered by incubating bladder biopsy tissue and by using specific culture media or DNA technology. 19 Domingue et al. 20 detected gram-negative bacterial DNA in 29 percent of bladder biopsies of patients with interstitial cystitis and sterile urine, but not from control patients. Potts et al.21 reported positive cultures for Urea urealyticum in 48 percent of 48 women presenting for evaluation for possible interstitial cystitis. Other fastidious organisms include Helicobacter, Campylobacter, and Mycobacterium. 22 If infection is part of the development of interstitial cystitis, it likely plays a minor role. It has been suggested that acute infection could serve as a trigger for the development of a reflex sympathetic dystrophy in the bladder, eventually leading to the SEPTEMBER 200 I

characteristic neuro-inflammation seen in interstitial cystitis. 23 Even with sophisticated culture and detection techniques, organisms have not been consistently cultured nor have any clear patterns of infecting organism emerged. NEUROLOGIC DISEASE

The bladder wall in interstitial cystitis typically shows high concentrations of nerve fibres 24 surrounded by abundant mast cells. 25 Such findings have led to the speculation that interstitial cystitis is a disease of primary neurogenic etiology.26 Investigators speculate that neuropeptides from bladder wall neurons in diseased individuals are released in higher than normal concentrations. The release of these potent neuropeptides (such as Substance P) results in the recruitment and activation of mast cells, causing secretion of their mediators. 26 Mediators such as histamine and prostoglandins are associated with inflammation, nocioception, vasopermeability, and direct cell and tissue damage and later fibrosis. Histamine also induces pain through stimulation of afferent C-fibres. 26 Though perhaps only an indirect marker of inflammation, nitric oxide has been shown to be present in markedly elevated bladder concentrations in patients with interstitial cystitis as compared to healthy controls.27 Other mast cell triggers besides neuropeptides exist, including bacteria, cyrokines, and possibly estrogen. 28 Theoharides et al 28 have shown that bladder mast cells have increased expression of high affinity estrogen receptors. The authors speculate that fluctuating estrogen levels could trigger mast cell degranulation in the bladder wall and thus explain the female preponderance of the interstitial cystitis, and the premenstrual worsening of symptoms experienced by many patients with the disease. CLINICAL PRESENTATION

m

SYMPTOMS

Interstitial cystitis is characterized by urinary urgency, voiding frequency, and suprapubic pain (Table 2). Ninety percent of patients with interstitial cystitis complain of urinary frequency and urgency. 1 A typical patient voids 16 times daily.29 Hematuria has been reported in up to 30 percent of patients. 3D Urinary incontinence is uncommon. 29 The pain of interstitial cystitis is generally suprapubic, though it can also occur in the pelvis, groin, vagina, or perineum. 29 Typically, the pain worsens with bladder filling and is relieved by voiding, which distinguishes it from the pain of acute bacterial cystitis, in which pain usually worsens as the bladder empties. 1 The pain is usually described as burning in nature. The natural history of the disease includes spontaneous exacerbations and remissions. In a mail survey, Held et aL31 reported that 50 percent of patients with interstitial cystitis experienced at least one spontaneous remission untelated to therapy with a mean duration of remission of eight months. The Interstitial Cystitis Data Base (ICDB) Study Group JOGe

was created in 1993, with the objective of determining the natural history of the disease and long-term response to various treatments. This cohort included 637 patients; 91 percent of its participants were female and 93 percent of the cohort were Caucasian. Nearly 40 percent of patients described daytime urinary frequency of 15 times or more, and more than 20 percent reported voiding at least four times per night. Almost half (48%) of patients noted constant urgency and 24 percent reported having severe pain? Propert et al 8 reported no change in symptom severity over four years of cohort follow-up. QUALITY OF LIFE

The symptoms of interstitial cystitis create substantial psychological, social, and hygienic problems, and can diminish the quality of life of the patient and her family.2,6,23,32 Michael et aL32 recently documented reduced quality oflife, as assessed by a validated questionnaire, in 99 women with interstitial cystitis from among the larger cohort of the Nurses Health Study. Chronic pain and sleep loss can lead to depression. 2 Slade et aL33 reported that 63 percent of patients with interstitial cystitis were unable to work full-time. Disease sufferers contemplate suicide three to four times more often than the general population. 6 GYNAECOLOGIC AsPECTS

In addition to the suprapubic and pelvic pain many women experience in interstitial cystitis, they experience symptoms of other gynaecologic problems (Table 2). Dyspareunia can occur,34 and probably relates to the mechanical effects of intercourse on the inflamed bladder wall. Postcoital discomfort can last for hours or days.34 Patients with interstitial cystitis may describe vulvar pain similar to that of vulvar vestibulitis. Chaim et al 35 recently reported an increased number of mast cells in excised perineal tissues of women with vestibulitis, suggesting a possible common etiology for both diseases. However, the incidence of coexistent vulvar vestibulitis in patients with interstitial cystitis has been observed to be no higher than 3.5 percent. 36 .37 TABLE 2

SYMPTOMS OF INTERSTITIAL CYSTITIS

Common • urinary urgency • daytime urinary frequency (> 8 voids) • nocturia (> I VOid) • suprapubic pain Uncommon

• hematuria • pelvic pain • vaginal/perineal pain • groin pain • dyspareunia • urinary incontinence

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Up to 35 percent of women complain of a premenstrual exacerbation of interstitial cystitis-related symptoms. 34 Theoharides et al. 28 have suggested that this observation relates to estrogen-induced degranulation of bladder wall mast cells, described above. The premenstrual exacerbation of symptoms, along with pelvic pain and dyspareunia, can lead to diagnostic confusion with endometriosis. Westney et al. 38 noted that in 70 percent of cases of documented bladder endometriosis, the symptoms were identical to those of interstitial cystitis. Interstitial cystitis should always be considered in women with such symptoms and normal findings at laparoscopy. The effect of pregnancy on interstitial cystitis has not been prospectively studied. Anecdotal reports suggest that a substantial number of patients experience stabilization and improvement while pregnant. 34

TABLE 3

DIAGNOSIS OF INTERSTITIAL CYSTITIS

Essential • history • physical exam with pelvic exam • urine culture • urine cytology Optional • vaginal wet mount for Trichomonas/yeast • cervical and urethral cultures for Chlamydia/Gonorrhea • voiding diary • cystoscopy with hydrodistension under general anesthesia • bladder biopsy • cystometry • potassium sensitivity test

AGGRAVATING FACTORS

As there are no blinded, controlled restriction-provocation studies on the effects of different foods on the course of interstitial cystitis, strict dietary recommendations cannot be made. Observational data, however, suggests that some foods exacerbate symptoms, including caffeine, citrus fruits, wine and other alcoholic beverages, chocolate, yogurt, sour cream, and bananas. 39 KozioF reported that 50 percent of patients with interstitial cystitis found acid-urine-producing foods to exacerbate symptoms. Gillespie40 reported a marked reduction in pain and frequency in 10 patients after dietary restriction of acid-urine-producing foods and foods high in tyrosine, tyramine, aspartate, and phenylalanine, with reintroduction of these foods triggering worsening of symptoms. Conversely, Bade et al. 41 identified no specific food preferences or avoidances in 16 patients with interstitial cystitis. DIAGNOSIS

Clearly, not everyone with urinary urgency or frequency or pelvic pain has interstitial cystitis, and its symptoms overlap with those of other diseases such as endometriosis and PlO. The diagnosis of interstitial cystitis cannot thus be based solely on symptoms. The history should exclude other causes of cystitis, including radiation, chemotherapy, and tuberculosis. A careful pelvic examination is necessary to rule out reproductive tract disease. Tenderness on palpation of the anterior vaginal wall may point to underlying interstitial cystitis. A vaginal wet mount should be performed to rule out trichomoniasis or candidiasis, and cervical and urethral swabs should be taken for chlamydiae and gonorrhea. Urine culture and cytology are mandatory. The diagnosis of interstitial cystitis should be considered in the presence of symptoms (Table 3), and in the absence of another more clearly defined disease (Table 4). The role of cystoscopy in the diagnosis of interstitial cystitis is unclear, and the role of bladder wall biopsy even less clear. JOGC

There is no uniform agreement regarding the cytoscopic and histopathologic features for the disease. 42 Currently, mast cell counts from bladder wall biopsy specimens are thought to have little or no diagnostic value. 19 Many clinicians simply consider interstitial cystitis to be a diagnosis of exclusion in the absence of other identifiable pathology. A diagnostic dilemma definitely exists. In an effort to clarifY the issues, the National Institute ofDiabetes and Digestive and Kidney Diseases (NIDDK) developed consensus criteria in 198843 for the diagnosis of interstitial cystitis (Table 5). Though these criteria were not meant to define the disease but to ensure that groups of study patients would be relatively comparable and homogeneous, they have now become so well accepted that they form the basis for diagnosis. They may, however, be too restrictive for routine clinical use, particularly because cystoscopy is mandated. Hanno et al. 44 demonstrated that strict application ofNIDDK Criteria would have missed 60 percent of patients regarded by researchers as definitely having or likeTABLE 4

DIFFERENTIAL DIAGNOSIS

Gynaecologic • endometriosis • pelvic inflammatory disease • vulvovaginitis • vulvar vestibulitis Urologic • urinary tract infection • radiation cystitis • chemotherapy-related or chemical cystitis • tubercular cystitis • bladder carcinoma • detrusor instability

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ly to have the disease. In the ICDB Study Group, only 45 percent of enrolled patients had cytoscopic confirmation of disease. 44 A recent study has led to further confusion surrounding the value of abnormal findings on cystoscopy. Waxman et al. 45 recently reported characteristic cystoscopic findings of interstitial cystitis with hydrodistension in nine of 20 healthy asymptomatic women undergoing tuballigation. The question of the necessity of cystoscopy, with or without biopsy, for diagnosis thus remains unanswered. TABLE 5

REVISED NIDDK* CONSENSUS CRITERIA FOR INTERSTITIAL CYSTITIS43

At least one of these symptoms must be present: • Pain linked to the bladder • Urgency to urinate

At least one of these findings must be present at cystoscopy: • Diffuse glomerulations in at least three quadrants of the bladder • Classic Hunner's ulcer (findings by cystoscopy under GA with hydrodistension to 80-100 cm water pressure for one to two minutes. The bladder must be distended up to two times for evaluation.)

The following criteria exclude a diagnosis of interstitial cystitis: • • • • •

• • • • • • • • • • •

age less than 18 years daytime frequency less than 8 times/day absence of nocturia less than two times/night bladder capacity greater than 350 ml while awake absence of intense urge to void with bladder volume to 100 ml gas or 150 cc water using a medium fill rate during cystometry demonstration of systolic (phasic) involuntary detrusor contractions on cystometry at medium fill rate duration of symptoms less than 9 months symptoms relieved by antimicrobial, urinary antiseptic, anticholinergic or antispasmodic medications urinary tract infection in past three months active genital herpes or vaginitis urethral diverticulum bladder or lower ureteral calculi uterine, cervical, vaginal, or urethral cancer history of cystitis related to cyclophosphomide or similar chemicals, or radiation history of tuberculous cystitis history of benign or malignant bladder tumours

* NIDDK

= National

Institute of Diabetes and Digestive and

Kidney Diseases Adapted from Gillenwater J, Wein A. Summary of the National Institute of Arthritis, Diabetes. Digestive and Kidney Diseases Workshop on interstitial cystitis. JUral 1988; 140:203-6.

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DIAGNOSTIC TOOLS

For further evaluation of the patient presenting with urinary urgency, frequency, or suprapubic pain, the following may be helpful in making the diagnosis of interstitial cystitis. INTERSTITIAL CYSTITIS SYMPTOM INDEX AND PROBLEM INDEX QUESTIONNAIRE

The O'Leary-Sant Interstitial Cystitis Symptom Index and Problem Index46 is a validated, patient-administered scoring tool. It comprises two indices. The Symptom Index assesses symptoms objectively (to a maximum possible score of20), and the Problem Index assesses the effect of symptoms upon quality of life (to a maximum possible score of 16). A total score of less than five on either index essentially rules out the diagnosis of interstitial cystitis. The index scores are not meant for use as a screening tool, but rather as an adjunct to diagnosis. They also provide an objective and reliable tool to follow a patient's response to treatment. VOIDING DIARY

Objective documentation of urinary frequency and nocturia through the patient's use of a voiding diary for two or three days may be helpful in diagnosis. A voiding diary can also provide information regarding fluid intake and output, and be useful as a patient education tool regarding behaviour modifications such as fluid restriction and toileting habits. CYSTOSCOPY AND HYDRO DISTENSION

When cystoscopy is performed for diagnosis, it is done under general anesthesia. The bladder is filled with water under passive gravity infusion at a pressure of 60 to 80 cm water for two to three minutes. With hydro distension, mucosal pinpoint hemorrhages (glomerulations) ate seen in 90 percent of patients,? and classic Hunner's mucosal ulcerations are seen in 10.5 percent of patients? CYSTOMETRY

While urodynamics ate not considered necessary for diagnosis, typical findings at cystometry in patients with interstitial cystitis include early sensation on filling and reduced bladder capacity. 8 As with cystoscopy, urodynamics are perhaps most usehll in excluding other bladder pathology (i.e., detrusor instability). POTASSIUM TEST

Parsons et al. 18 proposed the use of an intravesical potassium test for the diagnosis of interstitial cystitis (Table 6). Their study included 272 participants. A positive potassium test was recorded in 75 percent of diseased patients as compared to four percent in the control group. Unfortunately, the test was negative in 25 percent of patients with interstitial cystitis, raising questions about its sensitivity and specificity as a diagnostic tool. Chambers et al.47 recently reported a sensitivity of 69.5 SEPTEMBER 200 I

percent and a specificity of 50 percent using the potassium test as compared to cystoscopy. It would therefore appear to have only a limited role in the diagnosis of interstitial cystitis.

TABLE 7 TREATMENT OPTIONS FOR INTERSTITIAL CYSTITIS Pharmacological I. Oral Pentosan polysulfate sodium Hydroxyzine hydrocholoride Amitriptyline 2. Intravesical Dimethyl sulfoxide Hyaluronic acid Other

TREATMENT

I'

i

Treatment should address the relief of symptoms, the regeneration of the bladder lining, and the restoration of the quality of life. Pharmacological, surgical, and supportive therapies exist to achieve these objectives and are probably most effective when used in combination (Table 7). A systematic approach to treatment (Figure 1) with a team of urologists, dietitians, physiotherapists, psychologists and nurse-clinicians coordinated by the primary care physician offers the best opportunity to achieve the objectives. PHARMACOLOGIC THERAPY

Surgical Hydrodistension Transurethral resection Substitution cystoplasty Diversion/conduit

Pharmacologic therapy to treat interstitial cystitis is confined to a few oral and intracystic medications directed to control pain, restore the bladder lining, and reduce mast cell-effect activation.

Supportive Bladder retraining Dietary changes Others

cystitis. PPS is the only drug to reverse the course of the disease by correcting the pathologic process. 48 The usual dosage is 100 mg three times a day. At three months, 40 to 42 percent of patients reported improvement, and at six months, 70 percent of patients were clinically better. 6,48 The dose may be increased to 200 mg three times a day. Unfortunately, 80 percent of patients relapse with discontinuation ofPPS.6 Adverse reactions (Table 8), including nausea and vomiting (5%), alopecia (1 %) and chest pain « 1%) occur in about six percent of patients. 49 Although side effects

ORAL THERAPY

Pentosan polysulfate sodium (PPS) is the only oral therapy specifically designed to regenerate the bladder epithelium and the only oral agent approved by the Health Protection Branch of Health Canada. 34 PPS is a macromolecular carbohydrate derivative that chemically and structurally resembles GAGs.34 The drug is taken on an empty stomach to maximize absorption and is excreted in the urine in an unchanged form. The molecules bind to the bladder mucosa where they ease pain, urinary frequency, and the other symptoms of interstitial

TABLE 6

POTASSIUM SENSITIVITY TESTIS STEP ONE

STEP TWO

40 ml H2 0 in bladder

40 ml KCL solution in bladder (40 meq KCL in 100 ml HP) Hold three minutes

Empty bladder

Hold three minutes

0

I

None

Severe

2

3

4

Empty bladder

Score pain / urgency

Score pain / urgency None

STEP FOUR

STEP THREE

5

0

Severe

I

2

3

4

5

If score from Step Two is two or more points greater than score from Step One, test is POSITIVE. The diagnosis of interstitial cystitiS should be considered. Adapted from Parsons CL, Greenberger M, Gabal L, Bidair M, Barme G. The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. J Urol 1998; 159: 1862-6.

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may lead to discontinuation of the drug, persistence with its use when alopecia occurs does not cause long-term hair loss. The process is limited and reversed simply by stopping the drug. 49 Hydtoxyzine hydrochloride, an antihistamine, may be effective for patients with seasonal allergies 49 . In the presence of mast-cell activation in bladder mucosal biopsies hydroxyzine hydrochloride may also be effective. 34 ,48.50 Hydroxyzine hydrochloride is taken as a dose of25 to 50 mg twice a day with a common side effect of somnolence49 . The interstitial cystitis symptoms may be relieved by hydroxyzine hydrochloride, but hydroxyzine hydrochloride is not effective in regenerating the

mucosallining49 . There are no placebo-controlled, randomized studies comparing hydroxyzine hydrochloride to PPS or placebo. Tricyclic antidepressants (TCA) such as amitriptyline, extensively used in the treatment of chronic neurogenic pain, have been demonstrated as effective in alleviating the pain of interstitial cystitis. 5l The starting dose is 25 to 50 mg nightly, and may be increased gradually to 150 mg nightly. TCAs should not be given to patients with arrhythmias due to the risk of sudden cardiac death. The anticholinergic effects include dry mouth, dry eyes, and constipation. Weight gain is a major reason for discontinuation of the drug.

FIGURE I

TREATMENT PROCESS FOR INTERSTITIAL CYSTITIS

Hydrodistension at diagnostic cystoscopy ,

Primary approach

If allergenic history

Pentosan polysulfate sodium and dietary changes

If adverse reactions occur

Hydroxyzine hydrochloride and dietary changes

Pain Control

Amitrip~Hl'fe~~o~Jj~~i~s ~fl(J· . . supportive measures.

"

Poor or no response or adverse reactions

Intravesical DMSO cocktail or hyaluronic acid Poor or no response or adverse reactions

etfiletm inrtttmavesical tfilelmap)l1 if aliailalle Poor or no response or adverse reactions

L-arginine,52 a nitric acid donor, has shown promise as a treatment for interstitial cystitis, but has not yet been approved in Canada.

TABLE 8

ADVERSE REACTIONS TO PENTOSAN POLYSULFATE SODIUM (1-4%) • Alopecia • Diarrhea, nausea • Headache • • • • •

INTRAVESICAL THERAPY

Dimethyl sulfoxide (DMSO) has been used for more than 20 years as an intravesical treatment for interstitial cystitis and has been approved by the Health Protection Branch. 51 Hydrocortisone, heparin, bicarbonate, lidocaine hydrocortisone, or hyaluronic acid have been added to DMSO to produce a cocktail that appears to be more effective than DMSO alone in regenerating the mucosallining. 34 , 51 DMSO, in uncontrolled studies, produced symptomatic remission in up to 70 percent of patients with ulcerative interstitial cystitis and 90 percent of patients with nonulcerative interstitial cystitis for up to 24 months. 34,51 Four to eight treatments were given at intervals of one to two weeks. Unfortunately, 10 to 15 percent will recur. When used as a single agent, either heparin 34 or hyaluronic acid53 alone reduced symptoms in, respectively, 50 percent and 71 percent of cases, and when used in conjunction with DMSO, reduced the relapse rate. 34 Intravesical oxychlorosene sodium,54 bacillus CalmetteGuerin, PPS, and interferon have shown promise as rescue therapy for patients who fail to respond to DMSO monotherapy or cocktails, but must be considered experimental. 55

Rash Dyspepsia Abdominal pain Liver function abnormalities Dizziness

TABLE 9

TROUBLE FOODS FOR INTERSTITIAL CYSTITIS SUFFERERS ACID FOODS TO BE AVOIDED Apple juice Apples Apricots Cantaloupes Carbonated drinks Cayenne Chilies/spicy foods Citrus fruits (lemons, limes, oranges, etc., and their juices) Coffee Cranberries Ginger

Grapes Guava Lemon juice Peaches Pineapple Plums Rhubarb Strawberries Tea Tomatoes Vinegar Watermelon

SURGERY

FOODS HIGH IN TYROSINE, TYRAMINE, TRYPOTOPHAN,AND ASPARTATE TO BE AVOIDED Mayonnaise Anchovies Avocado NutraSweet (aspartame) Bananas Nuts Onions Beer Brewer's yeast Papaya Pickled herring Canned figs Pickles Caviar Pineapple Champagne Cheeses (hard and soft, Pork such as camembert, Prunes Raisins brie, tome) Chicken liver Rye bread Saccharine Chocolate Sour cream Cold cuts Corned beef Soy sauce Wines Cranberries Yogurt Fava beans Lentils Vitamins buffered with aspartate Lima beans

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At the time of diagnostic cystoscopy, hydrodistension induces the submucosal hemorrhages characteristic ofIC. This process, thought to damage tiny afferent nerve fibres,51 produces relief of symptoms in 20 to 55 percent of patients and is thus therapeutic as well.34,51 Unfortunately, the relief is temporary, lasting about six months. 45 Additional therapy is needed and oral PPS is the first, best option. Transurethral resection, fulguration, or laser ablation may eradicate localized disease such as a Hunner's ulcer, but is not effective for long-term resolution. 34 Transcutaneous electrical nerve stimulation is an option for refractory cases. 56 For about five percent of patients, supratrigonal cystectomy with substitution cystoplasty or total cystectomy with diversion are surgical options. 34,51,57 Pain relief is often dramatic, but symptoms of interstitial cystitis may be replaced by postoperative surgical pain or other symptomsY Surgical procedures are used for cases refractory to all other treatment modalities. SUPPORTIVE THERAPY

Supportive therapy begins with educating the patient and her family about the interstitial cystitis and the treatment options. Any available literature or Web sites should be provided to the patient. The Canadian Continence Foundation and the Canadian Interstitial Cystitis Society are excellent support groups. SEPTEMBER 200 I

Management should include backup options and follow-up plans to reassure the patient she is not going to be left alone and to encourage her to be active in her treatment. Dietary changes may ease or eliminate the symptoms in 50 percent of patients 58 and may augment other treatment options. The elimination of a single food, such as bananas or oranges or cranberry juice, may be effective for some patients, while others require complete elimination of the potential irritants through a strict diet. Diets eliminating caffeine, acidic fruits and their juices, carbonated beverages and foods high in potassium (Table 9) are available. 59 Timed voiding and bladder retraining programs may ease the frequency and the urgency associated with the suprapubic pain. 6o Some individuals may benefit from acupuncture, massage therapy, and stress reduction programs, and these options are worth exploring for selected patients before proceeding to radical surgery.51 CONCLUSION

The diagnosis and treatment of interstitial cystitis is difficult. Recognition of the symptoms in the presence of negative cultures, followed by timely referral to a urologist for assessment and treatment so that the diagnosis can be confirmed, improves the chances of symptom resolution. A systematic approach to treatment with a team of urologists, dietitians, physiotherapists, psychologists, and nurse-clinicians coordinated by the primary care physician offers the best opportunity to achieve the objectives. Educating and managing a patient with interstitial cystitis takes both time and effort, but is important to the restoration of her quality oflife. REFERENCES I.

2. 3. 4. 5. 6. 7.

8.

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The Canadian Consensus Conference on Menopause and Osteoporosis

This issue of the ]OGC includes a Self-Directed Learning Module on The Canadian Consensus Conference on Menopause and Osteoporosis. This module qualifies for credits under Section 2 of the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Don't miss this valuable selfdirected learning module on The Canadian Consensus Conference on Menopause and Osteoporosis. Supported by an unrestricted educational grant from

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