Interstitial Cystitis: Characterization and Management of an Enigmatic Urologic Syndrome

Treatment Update

TREATMENT UPDATE Interstitial Cystitis: Characterization and Management of an Enigmatic Urologic Syndrome J. Curtis Nickel, MD Department of Urology, Queen’s University, Kingston, Ontario, Canada The enigmatic urologic condition known as interstitial cystitis has an estimated prevalence of 0.01% to 0.50% of the female population. Its etiology is unknown but may involve microbiologic, immunologic, mucosal, neurogenic, and/or other, as yet undefined, agents. There is no gold standard for the diagnosis of interstitial cystitis; rather, it is a diagnosis of exclusion. It is impossible to provide a purely evidence-based treatment strategy, but review of available evidence suggests that conservative supportive therapy (including diet modification); oral treatment with pentosan polysulfate, amitriptyline, hydroxyzine, or cimetidine; and intravesical treatments with heparinoids, dimethyl sulfoxide, alkalized lidocaine, or bacille Calmette-Guérin may be effective in some patients. [Rev Urol. 2001;4(3):112–121] © 2001 MedReviews, LLC Key words: Interstitial cystitis • Cystitis • Frequency • Urgency • Chronic pelvic pain syndrome I nterstitial cystitis (IC) is an enigmatic syndrome that has perplexed and frustrated urologists for decades. It is a clinical condition, which by definition is characterized by urinary frequency, urgency, nocturia, and suprapubic (bladder and/or pelvic) pressure and/or pain1,2 in the absence of any identifiable cause, such as a bacterial infection. Despite millions of dollars of research funds expended by many committed researchers in the field, IC has defied our attempts to really understand its etiology and pathogenesis. Despite this uncertainty, the urologic profession and its associated research partners are developing therapeutic management strategies that benefit many of the patients suffering from this disease. Our goal as physicians should be to encourage exploration of new and innovative clinical approaches to this syndrome, continue to improve our personal understanding of it, and be willing to adapt and employ the newest evidence-based advances in our clinical practice. The Queen’s University Department of Urology Interstitial Cystitis Research Clinic has been active since the early 1980s, and we have seen 112 VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY Interstitial Cystitis due to significant differences in the methodologies and diagnostic criteria employed. The long-term longitudinal follow-up of 637 IC patients in the NIH Interstitial Cystitis Database Study7 supports the clinical observations that IC is a chronic disease and that current treatments do not appear to have a significant impact on symptoms over time. Table 1 NIDDK Research Definition of Interstitial Cystitis.15 Inclusion Criteria 1. Cystoscopy—glomerulations and/or classic Hunner’s ulcer 2. Symptoms—bladder pain and/or urinary urgency Exclusion Criteria 1. Bladder capacity greater than 350 cc on awake cystometry 2. Absence of an intense urge to void with the bladder filled to 100 cc during cystometry using a fill rate of 30–100 cc/min 3. Demonstration of phasic involuntary bladder contractions on cystometry using the fill rate described in number 2 4. Duration of symptoms less than 9 months 5. Absence of nocturia 6. Symptoms relieved by antimicrobials, urinary antiseptics, anticholinergics, or antispasmodics 7. Frequency of urination while awake of less than eight times a day 8. Diagnosis of bacterial cystitis or prostatitis within a 3-month period 9. Bladder or ureteral calculi 10. Active genital herpes 11. Uterine, cervical, vaginal, or urethral cancer 12. Urethral diverticulum 13. Cyclophosphamide or any type of chemical cystitis 14. Tuberculous cystitis 15. Radiation cystitis 16. Benign or malignant bladder tumors 17. Vaginitis 18. Age less than 18 years Diagnosis This is a research definition only (for inclusion of patients in clinical trials) and is not necessarily applicable to diagnoses made in clinical practice. The major difference in the less stringent ICDB inclusion criteria for the diagnosis of IC17 is that cystoscopy (and its related diagnostic criteria) is an optional criterion for entry into the ICDB study. The rigid urodynamic exclusion criteria in the NIDDK definition do not exclude patients from an ICDB IC diagnosis. IC, interstitial cystitis; ICDB, Interstitial Cystitis Database; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases. our understanding of this condition change dramatically over the last 2 decades. This experience in managing hundreds of IC patients in multiple basic science and clinical studies over the last 20 years has allowed the author to examine this medical condition not only from a research perspective but also in the context of a busy general urology practice. Epidemiology The true prevalence of IC is unclear; estimates vary from 10 cases per 100,000 in Finland3 to a range of 30 cases per 100,000 to 510 cases per 100,0004 in the United States. The prevalence in the Netherlands5 was estimated to be 8 to 16 cases per 100,000 female patients seen by urologists. The diagnosis appears to be made primarily in women (female:male ratio, 10:1). A recent questionnaire mailed to U.S. participants in the Nurses Health Study I and II suggested a prevalence of IC in these populations of women of between 52 and 67 per 100,000.6 The widely varying estimates of IC prevalence in the various studies are Although symptoms vary in frequency and intensity, patients diagnosed with the syndrome of IC present with a remarkably similar constellation of urinary frequency, urgency, nocturia, and suprapubic pain and perhaps dyspareunia.2,8–10 The symptoms appear to be exacerbated by stress11 and by some specific dietary items.12 The quality of life of IC patients is limited, particularly in the psychosocial dimensions.13 Since IC was first described by Hunner in 1914,14 there has been confusion as to the exact criteria upon which to base such a diagnosis. In the late 1980s, the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) convened workshops to develop diagnostic criteria for a research definition of IC.15 For the next decade, the diagnostic criteria established by this definition have stimulated significant research in a homogeneous group of patients.16 These diagnostic criteria for inclusion in an NIH-funded research study of IC are based on cystoscopic findings (glomerulation and/or classic Hunner’s ulcer) associated with bladder pain and/or urinary urgency and exclusion of other conditions that may cause similar symptoms (Table 1). Patients with IC who meet the NIDDK inclusion/exclusion criteria make up a fairly homogeneous population of IC patients; thus, the criteria have proven effective in clinical research studies, allowing compara- VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 113 Interstitial Cystitis continued Table 2 Suggested Initial Evaluation of a Patient with Suspected Interstitial Cystitis (IC) Mandatory Investigations 1. History 2. Physical examination (include focused examination) a. pelvic examination in women b. digital rectal examination in men 3. Urinalysis 4. Midstream urine culture Recommended Investigations 1. Cytology 2. Symptom index (ie, IC symptom index) 3. Voiding log/diary Optional Investigations 1. Cystoscopy ± hydrodistention ± biopsy 2. Potassium sensitivity test 3. Urodynamics 4. Pelvic ultrasound tive analysis of results. There is no doubt, however, that many patients with a clinical diagnosis of IC do not meet the strict NIDDK criteria.17 In fact, the so-called characteristic cystoscopic findings of IC are found frequently in normal women without symptoms of IC.18 Hanno and colleagues’ article on lessons learned from the NIH Interstitial Cystitis Data Base (ICDB) Study has shown that strict application of NIDDK criteria would have misdiagnosed more than 60% of patients regarded by researchers as definitely having or likely to have IC.17 The NIDDK criteria are too restrictive to be used by clinicians as the diagnostic definition of IC. One of the most striking differences between the ICDB study eligibility criteria and the NIDDK criteria was that baseline cystoscopy (and hydrodistention under general anesthesia) was an optional criterion for entry 114 VOL. 4 NO. 3 2002 into the ICDB study. Patients were also not excluded from the ICDB study on the basis of the stringent urodynamic exclusion criteria used by the NIDDK. It has been suggested that a better test for diagnosing IC is to employ a potassium sensitivity test, which lowing patients with IC. Physical examination must include a careful pelvic examination in women and a digital rectal examination in men. Urinary tract infection (ie, bacterial cystitis) must be ruled out first as the cause of the patient’s lower urinary tract symptoms. A negative culture The so-called characteristic cystoscopic findings of IC are found frequently in normal women without symptoms of IC. purportedly is a method for detecting abnormal epithelial permeability.19 Compared to their reactions to intravesically instilled water (40 mL), which causes no significant reaction, 75% of patients with IC vs 4% of controls demonstrated a marked sensitivity to the instillation of 40 mL of 40 mEq/100 mL potassium chloride. It is not recommended that this test be employed to make a definitive diagnosis of IC20–22 but either to confirm a clinical suspicion of IC or to identify IC patients who might benefit from specific therapy that would improve the impermeability characteristics of the bladder.22,23 Clinical evaluation of a patient suspected to have IC should start with a history and focused physical examination. The history should rule out concomitant diseases and include a very careful review of fluid intake (ie, amount of coffee, colas, etc) and output (a voiding diary kept for a day or so is extremely helpful). An inventory of pain and voiding symptoms is very important, both in the assessment and in the follow-up of patients with IC. Validated symptom indices, such as the O’Leary-Sant Questionnaire and Problem Index24 and the University of Wisconsin Interstitial Cystitis Scale25 have proven effective not only in clinical trials but also in clinical practice as important tools in assessing and fol- REVIEWS IN UROLOGY for uropathogenic organisms is a mandatory part of the investigation; a simple urinalysis and urine cytology complete the typical evaluation. A cystoscopy is required if the patient has gross hematuria, the cytology is atypical, or the history and physical examination suggest some other cause of the patient’s symptoms. Cystoscopy performed after hydrostatic dilation may show the characteristic features of IC, which include submucosal hemorrhages and petechiae, mucosal cracking with frank bleeding, and the rare Hunner’s ulcer. While cystoscopy is useful in ruling out other causes of bladder pain and irritability, the findings on cystoscopy are not necessarily definitive for IC,18,26,27 and the examination is not a mandatory initial diagnostic test. It should, however, be considered in patients with typical IC who do not respond to specific therapy.1010 Table 2 outlines some of the suggested mandatory, recommended, and optional investigations to be used in evaluating a patient suspected of having IC. Etiology and Pathogenesis The etiology and pathogenesis of IC are still undetermined. Determination of pathogenic mechanisms is complicated because IC is a clinical diagnosis and the role of biopsy of bladder tissue has been to confirm the exclu- Interstitial Cystitis sion criteria (eg, carcinoma in situ). There are no characteristic, specific, or defined pathologic criteria for the tissue diagnosis of IC.28 Similarly, since the syndrome is so diffuse in its clinical presentations (ie, severity of symptoms, cystoscopic findings, patients with IC.36 It has been suggested by our group37–39 and others33,40 that the GAG layer may have undergone a qualitative change rather than having a deficiency. It is very possible that the increased permeability seen in IC is a secondary phe- It is not inconceivable that a yet-to-be discovered microorganism...or microorganism byproducts may be the instigator of chronic inflammation. degree of histologic inflammation), other experimental markers for the disease have not proven to be consistent. However, over the last 2 decades, a number of attractive (but still hypothetical and not yet proven) hypotheses have been suggested, most based on at least some sound scientific methodology. The glycosaminoglycan (GAG) layer deficiency/leaky urothelium theory has a large following among the urology community and in fact has resulted in development of etiologically based treatment modalities for IC.29 The postulate is that there is a problem with the surface GAG layer that results in increased permeability to some unspecified toxic substance (eg, potassium) into the bladder wall, causing inflammation and pain.30–33 This theory, which remains quite popular, has not yet been proven. The original theory was promoted after it was shown that experimental bladder instillation of noxious substances (weak acid, detergents, and protamine) resulted in increased bladder permeability to urea and potassium. However, these substances may in fact have been affecting not only the surface GAG layer but also the urothelium itself (umbrella cells, tight junctions, etc). Our previous studies34,35 suggest that a GAG layer does exist on the surface of the bladder, but we were not able to show significant differences in nomenon rather than the primary etiologic mechanism. It has recently been demonstrated41 that urine contains heat-labile, cationic components of low molecular weight that bind to heparin and are cytotoxic to urothelial cells and underlying smooth muscle cells. These substances may be capable of causing mucosal injury and increased bladder wall permeability in susceptible patients. Urinary tract infection (UTI) and IC have many similar clinical characteristics, except that uropathogenic bacteria can be cultured from UTI patients, and these patients consequently have a far better response to antimicrobial therapy than IC patients. Patients with IC can have a history of UTIs,42 and most investigators will concur that IC patients do have at least the same incidence of symptomatic infection with uropathogenic bacteria as normal female patients. It has been suggested that IC may be due to small numbers of organisms in the urine (low-count bacteriuria), organisms such as Ureaplasma urealyticum, fastidious organisms not thought to be usually associated with clinical symptoms or even cryptic nonculturable microorganisms.43–46 Although current evidence has not supported an infectious etiology for IC,47,48 it is not inconceivable that a yet-to-be discovered microorganism (such as was identified in the Helicobacter pylori story in chronic gastritis) or microorganism byproducts may be the instigator of chronic inflammation. A number of investigators feel that IC has a primary immunologic etiology.49 Suggestions have been made that IC is either a nonspecific or a bladder-specific antibody- and/or cellmediated autoimmune disorder.50–52 However, there have also been suggestions that the lack of specificity seen in subsequent immunologic studies in IC makes it more likely that such observed responses are secondary to damage to bladder tissues rather than a primary cause of the inflammation.53,54 Mast cells are observed in histologic examinations of bladder specimens in IC. Their actual role in the etiology of the initial inflammation is unclear; however, there is no doubt that they play an important role in the pathogenesis of the continuing inflammation.55 The activity of mast cells is modulated by intrinsic nerves in the bladder wall and immunologic mechanisms (even hypersensitivity reactions), as well as by stress and female hormones. Release of biologically important mast cell mediators, which include those with vasoactive, nociceptive, pro-inflammatory, anticoagulant, enzymatic, angiogenic, and fibrogenic properties, triggered by many possible factors (immunoglobin E, sensory nerve stimulation, neural peptides, neural transmitters, allergens, antigens, lectins, cytokines, anaphylatoxins, bacterial toxins, physical factors, hypoxia, various chemicals and other toxins, etc), can set in motion and maintain an inflammatory scenario in the bladder. Although mast cells can be implicated in this process, there is no evidence to support the theory that IC is the manifestation of a primary mast cell disorder.56 There is currently increasing support for a possible neurogenic etiology VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 115 Interstitial Cystitis continued of IC, which has evolved from histopathologic examination of the bladder showing neural proliferation and chronic perineuritis in the bladder wall.57 This could be theorized to cause the cardinal symptoms of IC: pain, frequency, and urgency. The existence of such a sensory-nerverelated mechanism in the etiology and pathogenesis of IC has become an attractive theory advocated by a number of investigators.58 There is growing evidence that peripheral inflammation can lead to the generation of nerve impulses from the spinal cord that can promote and maintain inflammation in the end organ, in this case, the bladder.59 The association of IC with other pelvic floor disorders (lower gastrointestinal and gynecologic complaints) and chronic pain diseases60 adds further credence to a neurogenicneuromuscular etiology like that of these related disorders. It is our opinion that IC is likely the result of a multimodal cascade of events precipitated by some initiating event (any or all of those listed above) and propagated by immunologic and neurogenic mechanisms, culminating in a regional neuropathy characterized by pain and voiding disturbances (Figure 1). Treatment Therapy for IC is generally acknowledged as empiric, palliative, and therapeutically marginal. In the NIHsponsored ICDB study, there were almost as many therapies and/or combinations of therapies as there were patients enrolled (R. Landis: personal communication). However, numerous potentially effective therapeutic options have shown some efficacy compared to placebo in prospective randomized clinical trials. Supportive therapy. Once the diagnosis of IC is made, supportive therapy or even “watchful waiting" in 116 VOL. 4 NO. 3 2002 Initiating event (UTI, STD, trauma, allergy, toxin, systemic illness) Disturbance of bladder function (disruption of GAG layer) Absorption of urine constituents into bladder wall (K+, urea, immunogens, unspecified urine toxins) Inflammatory mediators ( ↑ cytokines, mast cell activation, inflammatory cell migration) Depolarization effect (sensory nerves) Acute inflammation Neurogenic injury Chronic inflammation Chronic neuropathy Pain + Irritative voiding symptoms Figure 1. The author believes that the pain and voiding symptoms associated with interstitial cystitis (IC) are the end result of a pluricausal cascade of events, triggered by an initiating event and culminating in a chronic bladder/pelvic neuropathy. GAG, glycosaminoglycan; STD, sexually transmitted disease; UTI, urinary tract infection. many cases is the treatment of choice. Patient education and empowerment promoting effective self-care strategies embody this approach.12,61 Stress reduction, anxiety reduction, exercise, and dietary modifications have all been found to be beneficial in some patients.62,63 Oral medications. Antibiotics. Since several research groups believe that microorganisms may be implicated in the pathogenesis of IC, a single trial of antibiotics can perhaps be justified. A prospective, randomized, placebo-controlled, 18-week trial of sequential antibiotic therapy (rifampin, doxycycline, erythromycin, metronidazole, clindamycin, amoxicillin, and ciprofloxacin for 3 weeks each) compared to placebo64 suggested that antibiotics alone or in combination may be associated with a decrease REVIEWS IN UROLOGY in symptoms compared to placebo but that this therapeutic approach did not represent a major advance in therapy for IC. Pentosan polysulfate. The synthetic sulfated polysaccharide pentosan polysulfate sodium (PPS) is believed to act by adhering to the luminal side of the bladder mucosa, thus maintaining or enhancing the permeability barrier of the bladder mucosa to various potentially toxic urine components.31 In a number of randomized, placebo-controlled trials, efficacy (defined as percentage of patients with 50% or greater improvement in overall evaluation) range from 28% to 42% vs 13% to 20% for placebo.65,66 A European study did show that patients treated with PPS had amelioration of some symptoms; however, the authors felt that Interstitial Cystitis they had failed to demonstrate objective efficacy in most parameters.67 Long-term evaluation of patients who received PPS in the open-label compassionate-use program demonstrated that PPS is a well-tolerated medication and that improvement of symptoms in 62% of selected treatment period. Although increasing the dose of PPS did not appear to improve efficacy in most patients, it was well tolerated. Moreover, the trial showed that the improvement noted with treatment continued to increase over the 32-week treatment period without plateauing and at 32 It appears that increasing the duration of therapy with PPS is more important in amelioration of IC symptoms than increasing the standard dose. patients persists for 6–35 months.68 This is not a universally accepted conclusion, as another study69 evaluating long-term follow-up data in 97 patients with IC found that PPS benefited only between 6.2% and 18.7% of patients. The only baseline factor predicting response to PPS in this study was less-constant pain. A recent meta-analysis of all major studies comparing PPS to placebo70 concluded that PPS was more efficacious than placebo in the treatment of pain, urgency, and frequency associated with IC but not significantly different from placebo in treating nocturia associated with IC. The diagnosis of chronic nonbacterial prostatitis, or, as it has been recently described, chronic pelvic pain syndrome in men, has many characteristics in terms of pain and voiding symptoms similar to those noted in the diagnosis of IC.71 A recent study evaluating PPS in men with CPPS noted significant improvement in symptoms in over 50% of subjects.72 The results from a large, randomized, placebo-controlled study comparing PPS to placebo in men with a diagnosis of CPPS should be available in 2002. The largest prospective randomized trial73 ever undertaken in IC was designed to evaluate the safety and efficacy of higher doses (300, 600, and 900 mg/day) during a 32-week weeks of therapy was far superior to the response seen in the placebo arm of any study ever reported in IC. It appears that increasing the duration of therapy with PPS is more important in amelioration of IC symptoms than increasing the standard dose. Hydroxyzine. Early clinical experience with hydroxyzine, a heterocyclic piperazine H1-receptor antagonist, suggests that this drug has some clinical efficacy in patients with biopsydocumented bladder mastocytosis/ mast cell activation and a history of allergies.74 In one study employing increasing titrated doses up to 50 mg at night and 25 mg in the morning, a 30% symptom improvement was noted.75 Results from the first NIH randomized placebo-controlled trial comparing hydroxyzine to placebo in IC should be available in 2002. been from 64% to 90%,76,77 but this drug has never been compared to placebo in a randomized study. Other. Other oral agents, such as cimetidine,78 quercetin,79 methotrexate,80 suplatast tosilate (a new immunoregulator),81 nifedipine,82 and L-arginine83 have also had limited efficacy reported in initial small studies. Cimetidine84 and quercetin85 appeared to be more effective than placebo in subsequently reported small randomized trials, but L-arginine failed to show significant clinical efficacy when subjected to randomized placebo-controlled trials.86,87 It remains important to confirm initially reported favorable results by subjecting any such medication to an adequately powered placebocontrolled study. Gabapentin, an antiepileptic agent, can be considered as an adjunctive treatment for the pain of IC.88 Opioid therapy for chronic pain control in patients with refractory disease is an effective, acceptable, but quite desperate measure. Intravesical therapy Dimethyl sulfoxide. Dimethyl sulfoxide (DMSO) has pharmacologic properties including anti-inflammatory, analgesic, collagen dissolution, and muscle relaxant action and effects on mast cell histamine release.89 Studies in Results from the first NIH randomized placebo-controlled trial comparing hydroxyzine to placebo in IC should be available in 2002. Tricyclic antidepressants. Tricyclic antidepressants have multiple mechanisms of action, including central and peripheral anticholinergic actions, blockage of serotonin and norepinephrine reuptake, and antihistaminic properties, which is believed to benefit patients with IC. Reported success rates with use of amitriptyline have our institution90 comparing DMSO to saline showed 93% objective improvement and 53% subjective improvement, vs 35% and 18%, respectively, for saline placebo. Intravesical DMSO (singly or in combination with other agents) is one of the mainstays in the pharmacologic treatment of IC.91 In a small (n = 21) randomized trial, VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 117 Interstitial Cystitis continued intravesical DMSO appeared to be superior to another possibly effective intravesical therapy, bacille CalmetteGuérin (BCG) (see later).92 Heparinoids. Intravesical heparin and hyaluronic acid are prescribed for the same theoretical reasoning as oral pentosanpolysulfate (to maintain or enhance the activity of the bladder’s own mucopolysaccharide lining), and both have been shown from studies performed in our insti- of IC. In a small, randomized, placebocontrolled study,98 twice as many patients in the group treated with PPS (4 of 10) had clinically significant improvement as in the group treated with intravesical saline (2 of 10). BCG. Intravesical BCG has shown some promise in clinical trials performed by one group in particular.99,100 Results with 6 weekly treatments were a 60% response rate in 15 patients treated with BCG, compared Surgical therapy for IC is an absolute last resort, after every other therapeutic modality has been tried and failed. tution93–96 to have some benefit. These heparinoid drugs also have other properties: adherence inhibition of immune complexes to polymorphonuclear cells, inhibition of leukocyte migration and aggregation, regulation of fibroblast and endothelial cell proliferation, enhancement of connective tissue healing, and scavenging of reactive oxygen species,94 which may also contribute to their action in IC patients. Results from a study undertaken in our institution97 have shown that the combination of intravesical DMSO and heparin is superior to DMSO alone for the longterm maintenance of its beneficial response. Intravesical PPS may also be an effective option for the treatment to a 27% placebo response rate in 15 control patients.99 Most patients who responded favorably continued to have an excellent response during a follow-up ranging from 24 to 33 months.100 In a subsequent randomized clinical trial, BCG did not produce as effective an amelioration of symptoms as intrave sical DMSO.92 A large multicenter NIH study is presently under way that should determine the ultimate efficacy and safety of BCG as a treatment in IC. Other. Intravesical lidocaine has been reported anecdotally as a “rescue" medication for patients in severe distress. We recently reported on the pharmacokinetics of intravesical lidocaine and its enhanced uptake with concurrent alkalization.101 In our small pilot study, this resulted in significant pain relief in patients whose IC had become refractory to all other treatment modalities.101 Intravesical resiniferatoxin (RTX), an ultrapotent capsaicin analog, has been shown to decrease pain and improve symptoms in patients with IC compared to placebo in a small randomized trial.102 A small randomized placebocontrolled trial comparing intravesical oxybutynin with saline103 demonstrated significant improvement in both groups, but the improvement was more evident in the group treated with intravesical oxybutynin. Electromotive drug administration has been reported to improve the efficacy of some intravesical therapies.104 Surgical therapy. Surgical therapy for IC is an absolute last resort, after every other therapeutic modality has been tried and failed.105,106 Most clinicians with experience in IC feel that the best procedure is a supravesical diversion, usually with a cystectomy. Pelvic pain can persist despite cystectomy,107 further evidence for a chronic neurogenic etiology for the condition. Patients who have undergone surgery for IC appear to have more long-term complications than patients who have had similar surgery for malignancy.108 Alternative therapies. Transcutaneous electrical nerve stimulation (TENS)109 Main Points • Interstitial cystitis (IC), a chronic disease, is clinically defined by the presence of urinary frequency, urgency, nocturia, and suprapubic pressure and/or pain but remains a diagnosis of exclusion. • Validated symptom indices are effective in clinical practice for assessing and following patients. • Characteristic cystoscopic features of IC include submucosal hemorrhages and petechiae, mucosal cracking with frank bleeding, and the rare Hunner’s ulcer. • Although a number of attractive (but still hypothetical and not yet proven) etiologic hypotheses have been suggested, there is insufficient evidence to support any of them over the others. • Therapy for IC is empiric, palliative, and, in many cases, therapeutically marginal. • Numerous potential treatments have shown some efficacy compared to placebo, especially when applied as multimodal therapy. 118 VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY Interstitial Cystitis ceed in ameliorating the patient’s symptoms. Commitment, empathy, diagnostic awareness, willingness to consider multimodal therapies, and reasonable therapeutic expectations on the part of both the physician and the patient appear to be the key to successful management of this condition. The therapeutic algorithm followed in the Queen's University Interstitial Cystitis Clinic is presented in Figure 2. Clinical diagnosis of interstitial cystitis Conservative treatment* Urgency/frequency Pain (main symptom) (main symptom) Allergic history (seasonal, drug, food) Antispasmodics† Hydroxyzine Oral therapy Intravesical therapy Pentosan polysulfate DMSO ± heparin‡ [Note: Dr. Nickel serves as a consultant for and has received research support from the Alza Corporation] References 1. Amitriptyline Other§ Surgery# *Diet and lifestyle modifications. †Rarely benefits patients with IC but sometimes reduces irritative voiding symptoms. ‡After six treatments authors continue intravesical heparin or oral pentosan polysulfate maintenance. §Intravesical alkalized lidocaine or BCG, oral cimetidine or quercetin. #Hydrostatic bladder dilation under general anesthetic; urinary diversion/cystectomy considered only as very last resort. 2. 3. 4. 5. Figure 2. The treatment algorithm employed by the Queen’s University Interstitial Cystitis Clinic for interstitial cystitis (IC). Treatments are not necessarily discontinued but may be prescribed concurrently (multimodal therapy). BCG, bacille Calmette-Guérin; DMSO, dimethylsulfoxide. and peripheral afferent nerve stimulation (Stoller Afferent Nerve Stimulation or SANS)110 may benefit some patients in whom conventional therapy has failed. Other uncontrolled studies111–115 have suggested that percutaneous sacral nerve root neurostimulation or neuromodulation improves symptoms in patients with IC. Since the end result of IC is pain and irritative voiding symptoms, likely through some form of inflammatory and/or immunologically mediated neurogenic cascade, neuromodulation therapies may hold promise for alleviating the symptoms of IC. Multimodal therapy. Although never substantiated by prospective randomized clinical trials, it appears to many experts in the field of IC management that multimodal therapy, 6. that is, employing a number of potentially effective treatment modalities simultaneously, is superior to the usual plan of employing a consecutive series of failed therapeutic options.116 It is important that future trials in IC consider the potential efficacy of combination or multimodal therapies. 7. 8. 9. 10. 11. A Practical Management Strategy How does a busy urologist distil the conflicting evidence in regard to the etiology and treatment modalities associated with IC? His or her role must be to have an open mind, a sound understanding of the clinical syndrome, a certainty of how to make the diagnosis, a rational treatment strategy, and a willingness to modify his or her standard plan if the management algorithm does not suc- 12. 13. 14. 15. 16. Nigro DA, Wein AJ. Interstitial cystitis: clinical and endoscopic features. In: Sant GR. Interstitial Cystitis. Philadelphia: LippincottRaven; 1997:137–142. Nickel JC. Interstitial cystitis. Can J Diagn. 1996;13:27–28. Oravisto KJ. Epidemiology of interstitial cystitis. Anals Khir Gynecol Fen. 1975;64:75–77. Jones CA, Harris MA, Nyberg L. Prevalence of interstitial cystitis in the United States. J Urol. 1994;151:423A. Bade JJ, Rijcken B, Mensink HJA. Interstitial cystitis in the Netherlands: prevalence, diagnostic criteria and therapeutic preferences. J Urol. 1995;154:203–208. Curhan GC, Speizer FE, Hunter DJ, et al. Epidemiology of interstitial cystitis: a population based study. J Urol. 1999;161:549–552. Propert KG, Schaeffer AJ, Brensinger CM, et al. A prospective study of interstitial cystitis: results of longitudinal follow up of the interstitial cystitis data base cohort. The interstitial cystitis data base study group. J Urol. 2000;163:1434–1439. Messing EN. The diagnosis of interstitial cystitis. Urology. 1987;29(suppl):4–7. Hanno PM. Diagnosis of interstitial cystitis. Urol Clin North Am. 1994;21:63–64. Nickel JC: Interstitial cystitis: etiology, diagnosis and treatment. Can Fam Physician. 2000;46:2430–2440. Lutgendorf SK, Creder KJ, Rothrock NE, et al. Stress and symptomatology in patients with interstitial cystitis: a laboratory stress model. J Urol. 2000;164:1265–1269. Whitmore KE. Self care regimens for patients with interstitial cystitis. Urol Clin North Am. 1994;21:121–130. Michael YL, Kawachi I, Stampfer MJ, et al. Quality of life among women with interstitial cystitis. J Urol. 2000;164:423–427. Hunner GL. A rare type of bladder ulcer in women: report of cases. Trans South Surg Gynecol Assoc. 1914;27:247–292. Gillenwater J, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases workshop on interstitial cystitis. J Urol. 1988;140:203. Simon LJ, Landis JR, Erickson DR, Nyber LM. The Interstitial Cystitis Data Base Study: concepts and preliminary baseline descriptive VOL. 4 NO. 3 2002 REVIEWS IN UROLOGY 119 Interstitial Cystitis continued statistics. Urology. 1997;49(suppl):64–75. Hanno PM, Landis R, Matthews-Crook Y, et al. Diagnosis of interstitial cystitis revisited: lessons learned from the National Institutes of Health Interstitial Cystitis Data Base Study. J Urol. 1999;161:553–557. 18. 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