PATIENT CONDITION
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INTERSTITIAL CYSTITIS Definition and Prevalence Interstitial cystitis (IC) is a clinical syndrome of urinary urgency/frequency and/or pelvic pain in the absence of an identifiable cause such as bacterial infection or a history of radiation to the bladder. In the past, it was believed that IC affected the bladder only, and was a relatively uncommon problem. Recent data have transformed both our definition of IC and our understanding of its prevalence.   The traditional diagnostic criteria for IC1, which were developed for research purposes, describe the intense and unremitting pain and urinary urgency of advanced disease. IC tends to develop gradually, however, as we will describe in the Presentation section. Advanced cases represent only perhaps 2% of the individual patients who have the disease. In the majority (98%) of affected patients, IC probably goes unrecognized when the traditional diagnostic criteria are used. In addition, new data indicate that IC may affect lower urinary tract tissues other than the bladder. The disease appears to arise from a pathophysiologic process that can also occur in the urethra and prostate, creating analogous conditions in those tissues; i.e. the disease we have called IC may affect large numbers of patients whose bladder-origin symptoms have been mistaken for signs of other disorders. Thus, there may be many cases of IC that are not reflected in the estimated from traditional urologic prevalence studies. The most recent such study, published by Curhan and coworkers in 1999, indicated that approximately 750,000 individuals in the United States may have IC2. For example, new data indicate that IC may be present in as many as 81% of gynecologic patients with chronic pelvic pain3. Chronic pelvic pain affects 14.7% of US women aged 18-50 years, or 9.2 million women, according to 1993 census numbers. If we extrapolate from our findings in gynecologic patients, then 81% of these women, or nearly 7.5 million, have IC. This total itself is probably a minimum number, because it reflects 10-year-old census data and includes neither patients who have urgency only nor young women who are between menarche and the age of 18. In 2002, a screening study was published in which the general public was screened with an IC symptom questionnaire. The data found indicates that IC may occur in approximately 1 of 4.5 women. Presentation IC is best regarded as a disease in a continuum. Typically, it is a gradually progressive disorder whose symptoms tend to be intermittent and relatively mild in the early stages. The symptoms generally become both more intense and more constant with time. In early IC, urinary urgency tends to be the principal symptom. IC patients who do have urgency may not report it because their frequency of urination is normal for them. As time goes on, pain of increasing severity becomes the more dominant symptom in IC. For most IC patients who decide to see a doctor, the driving force is pain rather than urgency. The pain of IC may be felt in any one or more locations in the pelvis in any combination, including the urethra, the vagina (in women), the penis, testes, and/or scrotum (in men), the suprapubic area, the lower abdomen, the lower back, and the inguinal area. It has been shown that the bladders of individuals with more advanced IC contain more pain fibers than those of individuals who have early or mild disease. In the early phases of IC, pain is usually intermittent. It presents as a sudden flare rather that may last for days to weeks and then remit. The character of IC symptoms varies not only from patient to patient but also from one day to the next in a single individual. Symptom severity depends not only on the stage of the disease but also on the activity of factors that provoke symptom flares, including hormonal fluctuations and seasonal allergies. As we will describe, variable pathophysiologic factors determine whether an individual has pain or urgency or both, as well as where the patient feels the pain. For all of these reasons, IC symptoms are often attributed to another urologic or gynecological problem. Early IC may be mistaken for recurrent bladder infections or chronic pelvic pain, particularly dyspareunia. Dyspareunia, in fact, is almost always due to IC. An IC patient may receive a diagnosis of "urethral syndrome," which actually is early IC; or "urethritis" or "nonspecific urethritis." Recent studies indicate there may be previously unsuspected numbers of IC patients among several other clinical populations. These include women who consult gynecologists for chronic pelvic pain, as mentioned above, as well as men with prostatitis and older men who have lower urinary tract symptoms (LUTS) and are being evaluated for possible bladder outlet obstruction (BOO). What underlies the symptoms in all these populations is a single pathophysiologic process, currently fragmented into multiple diagnoses. By traditional diagnostic criteria, only the patients with the most severe symptoms were given the diagnosis of IC. In fact, however, IC is probably present in the majority of patients who are under the age 50 and have urinary urgency and/or pelvic pain in the absence of any other identifiable cause. Pathogenesis In recent years, substantial progress has been made in understanding the development of IC. It may well be that IC encompasses a number of different etiologies, culminating in a bladder insult that ultimately results in the symptoms of pain and/or urinary urgency. Lymphatic, infectious, neurologic, psychologic, autoimmune, and vasculitic etiologies have been proposed for IC,13-20 but most of these are hypothetical, with little data to confirm or refute their role in the disease. A number of discoveries have helped to put some of the IC puzzle pieces in place. One of the more widely accepted theories is that there is a defective bladder epithelium with loss of the "blood-urine barrier" resulting in a leaky membrane.21, 22 The permeability of the epithelium to small molecules could explain the induction of symptoms, especially if the diffusing substances stimulate the depolarization of sensory nerves.23, 24 In particular, it has been shown that diffusion of potassium across the bladder epithelium could trigger the sensory nerve endings, resulting not only in symptoms, but even in disease progression due to tissue injury from toxic levels of this cation.25 Mast cells and their degranulation, vascular problems such as reflex sympathetic dystrophy, and probably neuroinflammation from upregulation of the sensory nerves also play a role in IC. Reduction of vascular perfusion may negatively affect mucosal, muscle and nerve nutrition and initiate a cascade of events that causes symptoms. Radiation is known to impair blood supply by injuring the microvasculature of organs and certainly, in the case of urinary bladder, leads to a syndrome that is basically IC with urgency, frequency, and altered epithelial permeability.26 Other profusion abnormalities such as reflex sympathetic dystrophy may result in a secondary decrease in blood flow that also triggers events leading to symptoms in the IC syndrome. Two studies have documented abnormal bladder perfusion in IC patients with bladder filling.76,77 Vascular injury could even be accelerated in IC because of reduced epithelial permeability regulation resulting in a potassium leak into the bladder interstitial space. This potassium would be directly toxic to the small blood supply of the subepithelial tissues, leading to further bladder destruction. A widely held theory concerning the pathogenesis of IC is that of an epithelial leak. The hypothesis is that the permeability regulatory mechanism of the superficial epithelial cells is impaired, resulting in the migration of solutes across the epithelium. There had been little data to support the concept that such a leak existed21 and a subsequent study was unable to confirm the initial observation that both normals and IC patients had abnormal findings in their tight junctions relative to ruthenium red penetration. The initial report involved only three patients and no controls, however, and was primarily an anatomic study. A well-controlled study in 56 patients provided data to support the hypothesis that the bladder surface in many IC patients may indeed leak solute.22 This data has been supported by subsequent investigations which employed an even more sensitive "leak assay" to screen individual patients for potential aberrations in permeability. From these studies, it was estimated that at least 70-75% of the patients could be determined to have a leaky epithelium.26, 28 The caveat here is that there are false negatives to the test (probably not false positives) and epithelial problems may be present in even more patients. In addition, this was a slightly skewed population with the patients who have a non-leaky epithelium being more difficult to treat and more likely to present to the tertiary care center. This latter concept is supported by the fact that other investigators have found similar responses to the potassium test. To date, the results of over1300 Potassium Sensitivity Tests in IC patients who have presented to urologists or gynecologists have been published. The data indicate that approximately 80% of individuals with IC have a positive PST; healthy controls are negative.3, 10, 26, 28-35 False positive PSTs are rare.10, 26, 28, 29, 36-39 These studies also suggest that a small part of this patient population has no detectable epithelial leak (by current technologies) and may represent some other problem, such as neurological inflammation. A negative PST confirms nothing, however, so it is not currently possible to estimate the actual percentage of "non-leakers." Prostititis An accumulating body of data suggests that prostatitis is a part of the IC complex. As mentioned above, abnormal bladder epithelial permeability has been demonstrated in males who have prostatitis, and this process is probably also ongoing in the prostatic ducts. Compared to women who have IC, men with prostatitis have approximately the same mean age at diagnosis (39-48 years old) and the same (or analogous) pain locations: the perineal, abdominal, testicular and penile areas. These men can also suffer from LUTS, dysuria, and have a rate of symptom flares associated with sex that is comparable to that of female IC patients. Pain locations reported by patients with prostatitis:
Diagnosis The diagnosis of IC is based on the presence of the characteristic pattern of symptoms of urgency, frequency, and/or pelvic pain in any combination. A patient may have only urgency or only pain, but most patients have elements of both. These may be persistent or intermittent, in any combination. Similar symptomatology could come from only a small number of disorders that should be ruled out: these are urinary tract infection, BOO in males, and rare instances of carcinoma of the bladder in the presence of hematuria. In addition to urinalysis, urodynamics, urine cytology and cystoscopy where appropriate, Potassium Sensitivity Testing can be helpful. Treatment As a result of dramatic changes in the therapy of IC in recent years, good disease control can now be achieved in up to 85-90% of patients with this disease. The key principle in the treatment of IC is to use multi-modality therapy to control the various aspects of the disease that are active at causing symptoms. Patients with mild IC may not need much therapy; those with severe disease may require multiple modes of therapy to control their complex of symptoms. A good rule of thumb is that the more active the disease, the more treatment the patient will need and the better success rate you will have. The range of therapies available for IC has been limited by the fact that many of the compounds that are active in the disease are generic. These generic compounds have not been, and probably never will be, studied in a controlled fashion. Perhaps the only medication that has been studied rigorously in multiple double-blind trials is pentosan polysulfate (Elmiron), discussed in detail below. Patients with IC receive the greatest benefit from a treatment program based on three principles:
Recommendations for therapy are discussed in detail below. Control of Epithelial Dysfunction Most people who have IC have a bladder epithelial dysfunction, which is reflected in a positive potassium sensitivity test. The cornerstone of treatment for patients with a dysfunctional epithelium is the category of heparin-like drugs, or heparinoids. Heparinoids have revolutionized the treatment of IC because they correct the problem of epithelial dysfunction, which occurs in the majority of patients with the disease. Two such medications are clinically available: heparin and pentosanpolysulfate (Elmiron). Heparin. Although heparin is given intravesically and has the drawback of requiring daily self-administration by the patient, it can be effective in up to 80-85% of patients.66 Currently, we use heparin in patients who are potassium sensitive and have failed oral therapy with pentosanpolysulfate, or patients who have very severe disease, and in these individuals we use a combination of oral and intravesical heparinoid therapy. The patient self-administering heparin at home should utilize a dose of 40,000 units heparin in 20cc sterile water, introducing the solution into the bladder and holding it only for as long as is comfortable. If the patient starts to experience pain, the bladder should be emptied immediately as it is important not to activate the pain cycle. Although the patient may be able to hold the solution in the bladder for only 20 minutes at first, this is a good starting point. Gradually, the patient will be able to hold the heparin solution in the bladder for longer periods of time, with the eventual goal of holding it comfortably for an hour. On heparin therapy, reasonable improvement of symptoms can be expected between 6 months and 2 years after initiation of therapy. As potassium sensitive individuals are the patients who are the most likely to respond to heparin, we recommend that they remain on heparin therapy for at least 3-4 years. Pentosanpolysulfate. Pentosanpolysulfate (Elmiron) is the only IC medication that has been studied rigorously in double-blind trials. Similar results have been obtained in four double-blind trials of pentosanpolysulfate; that is, that IC patients' response to the drug is twice the response to placebo, particularly with regard to pain.36-38, 49 In a longitudinal study that was published several years ago,67 it was reported that up to 75% of patients will respond to pentosanpolysulfate therapy when the drug is used for 6 months to 3 years. In this particular study, it was also determined that the patients stay better on the medication once improvement has been obtained. Because it basically corrects the major pathology associated with the disease, heparinoid therapy is the only mode of treatment on which the patients improve and stay improved. It has also been reported that if the patients are potassium sensitive that up to 82% will respond. When they are not, only 30% respond.31 The limitations of the early pentosanpolysulfate trials were that they were done for only 12 weeks on end-stage patients in low dose. Many studies of pentosanpolysulfate are in progress, and new and better dosing regimens will be emerging shortly. Although the recommended dose of pentosanpolysulfate (100 mg three times a day) is effective, ongoing trials show that higher doses such as 200 mg or even 300 mg three times a day are more effective. We usually employ, in females, 200 mg twice a day because it works well at this dose and is easier for patients to remember. It is our general recommendation that men be started on a dose of at least 200 mg three times a day. As reported in the double-blind studies mentioned above, the average patient begins to show reasonable improvement in 3-6 months, with good responses seen at 6-12 months. The more active and severe the IC and the longer the disease has been present, the longer it will take for pentosanpolysulfate to work. It is important for the clinician to bear in mind that while pentosanpolysulfate probably corrects the epithelial dysfunction at the bladder surface in a relatively short time, a basic improvement in symptoms will not be seen until neural deactivation takes place, which can be over months or years. In our experience, approximately 75% of patients who were continuously symptomatic for more than 6-9 months before treatment will relapse with symptoms after 3-4 months if they stop the medication once their symptoms improve. Once our patients have been symptom free for 6-12 months, we give them the choice of continuing or discontinuing the medication. The majority of our patients, at least 80%, elect to stay on therapy. Those who wish may be tapered off of medication and restart should they flare. Pentosanpolysulfate is safe and non-toxic. The principal side effect appears to be gastrointestinal distress, occurring in about 3-4% of patients. As this side effect may be related to the capsule rather than to the drug itself, we routinely have patients experiencing gastrointestinal side effects to take the medication with a small snack, or take it out of the capsule and put it into one ounce of water and drink the solution. Another pentosanpolysulfate side effect deserving mention is a rare form of alopecia known as alopecia reata, a patchy baldness. It is important to emphasize to the patient that the alopecia that can be associated with pentosanpolysulfate therapy will not cause complete baldness as in chemotherapy patients; rather, it is a completely reversible process. In those patients who do experience diffuse hair loss with pentosanpolysulfate, I advise continuing the medication because the alopecia tends to resolve. This is probably because the alopecia in many cases is associated with perimenopause rather than with the pentosanpolysulfate. Neurological Deactivation Another basic treatment principle in IC concerns a factor that urologists have been addressing for many years in sensory disorders of the bladder; that is, to inhibit the neurological activation that occurs and induces symptoms of urgency, frequency and pain. In a sense, this aspect of therapy treats the symptoms rather than the disease, but it is important to attempt to inhibit the neurological activation while the patient is undergoing heparinoid therapy to repair the epithelium and effect the natural regression of neural upregulation. This neurological aspect is the rate-limiting factor in a patient's response to treatment. It is not that heparinoid agents do not repair the bladder surface relatively quickly, but rather that these patients still have significant bladder volume sensitivity from the neurological activation. Such activation takes months or years to regress, and in some cases the regression never occurs. At the start of treatment, we place all of our patients on heparinoid therapy to address the epithelial dysfunction, plus an antidepressant to address the neural upregulation in perhaps 30-50% of them. The drugs we have found to be most active in controlling the neural upregulation of IC are amitriptyline68 and imipramine. The initial dose of either medication is 25 mg at bedtime. After the patient has been on this medication for 1-2 months, the dose can be increased to 50 mg. There is even a 10 mg pill for patients to take until they adjust to the very sedating effects associated with the medication. In an uncontrolled trial, Hanno reported about 50% of patients will respond to this therapy.68 In our experience, it is very useful in severely symptomatic IC patients, as it does help alleviate their discomfort. If the patients are unable to tolerate amitriptyline or imipramine because of the sedative side-effects and the appetite stimulation, we recommend using the selective serotonin reuptake inhibitors (SSRIs). We routinely use fluoxetine (Prozac) at doses of 10 or 20 mg per day. Rarely is it necessary to increase the dose. Sertraline (Zoloft) can also be used at doses of 50 mg per day, increasing to 100 mg per day if necessary. Nerve Stimulation Nerve stimulation has been used to treat both pain and the symptoms of urgency and frequency in patients refractory to other treatments. Transcutaneous electric nerve stimulation has been reported to improve pain in 26% of patients without ulcer disease and in 54% of patients with ulcer disease.95 Percutaneous sacral nerve root neuromodulation has also been reported to decrease daytime frequency, nocturia and pain while increasing voided volume.96 Unfortunately, neither technique has been compared to placebo. Further study is needed to determine the efficacy of nerve stimulation in the treatment of IC. Management of Allergies Allergies and mast cells play a substantial role in provoking the symptoms of IC. Mast cell activity is present in perhaps up to 70% of the patients with the IC syndrome. If mast cells are not regulated well, they will constantly muddy the waters, stirring up the symptom complex during allergy season or even whenever the patient is exposed to a problematic food allergen. Although a patient's epithelial dysfunction may be under good control (see above), his or her symptoms can activate completely back to the baseline during an allergy attack. Thus, when patients who are successfully managed on heparinoid therapy complain of symptom flares during the allergy season, the heparinoid therapy should not be discontinued, as it is essential to the long-term management of the patient. Instead, the symptom flares should be addressed with additional therapy; that is, antihistamines. Up to 70% of IC patients will need antihistamines in addition to heparinoid therapy to regulate the disease. The mast cells have been known to be active in this disease and antihistamines have been used for a number of used to help control symptoms.52, 69-71 As with other drugs or generics, the antihistamines have never been tried for treatment of IC in a controlled trial, and likely will not be. The best medication to use to treat mast cell degranulation chronically is a tricyclic compound, the drug hydroxyzine (Atarax, Vistaril) at the same dosing of imipramine and amitriptyline. A dose of 25 mg is more than sufficient to use chronically to inhibit mast cell degranulation. If the sedating effects of the 25 mg dose bother the patient when the medication is started, 10 mg doses are available. After 2-3 months of chronic therapy with this medication, the sedating effects disappear and the most powerful therapeutic effect of this particular antihistamine, the inhibition of mast cell degranulation, starts to become active. Hydroxyzine is the only antihistamine that works in this fashion and we have found it to be the best drug to use.72 During allergy season, the dose of hydroxyzine can be readily bumped to 50-100 mg per day with minimal sedating effects if the patient is accustomed to the medication. Alternatively, one can use any non-sedating antihistamine to help control the patient's allergy. Dimethylsulfoxide Dimethylsulfoxide (DMSO) was approved for use in IC in 1977 based on uncontrolled trials.73 DMSO appears to induce remission in 34-40% of the patients. The difficulty with DMSO is that it may induce an excellent remission in the first one to three cycles of therapy, but as an individual relapses and requires subsequent treatment, progressive resistance to its beneficial effects is seen in almost all patients for reasons unknown. For treatment, instill 50 cc of 50% dimethylsulfoxide into the bladder for 5-10 minutes. Longer periods are unnecessary since DMSO rapidly absorbs into the bloodstream. Instillations are performed on an out-patient basis or the patient can be taught to perform it themselves. The author recommends that patients receive 6-8 weekly treatments to determine whether a therapeutic response is achieved. It usually requires 2-3 months to obtain a good clinical response. If the patient has moderate or worse symptoms, continue the therapy for an additional 4-6 months once every other week. Remember, once DMSO is stopped, the patient is likely to become resistant to its use. Some patients will experience a flare of symptoms when DMSO is placed into the bladder. This phenomenon most likely is due to a detergent-like activity with DMSO destroying the superficial bladder umbrella cells and causing a significant increase in the epithelial leak. Nonetheless, DMSO may be very effective at treating these patients. Should the patient experience pain with DMSO, it is recommended that he or she receive intravesically 10 ml. of 2% viscous xylocaine jelly 15 minutes before placing DMSO. If this is not successful, then use an injectable narcotic or Toradol7 60 mgm or meperidine IM before the intra-vesical instillation. The flare of symptoms associated with DMSO usually disappears over 24 hours. As these patients receive subsequent treatments, the pain tends to diminish. Dietary Management Dietary management can be of benefit to patients who have IC. In general, we advise our IC patients to avoid potassium-rich foods; the four foods that our patients associate most often with aggravation of symptoms are citrus fruits, tomatoes, chocolate and coffee. All of these are extremely high in potassium, having a composition of 99% potassium and 1% sodium. We also advise our patients to avoid spicy foods or foods flavored with peppers. In addition, we often find it helpful for our IC patients to use either PolyCitra-K crystals, one packet twice a day, or Urocit-K 10 meq twice a day as a chelating agent in urine. Finally, we encourage our patients to try over-the-counter "nutriceuticals" such as Prelief in the management of IC, although there are no clinical data to substantiate their benefit. Neurostimulators Implantable neurostimulators have been reported to have some benefit in patients who have severe IC. These may also become useful in patients with disease that is refractory to more conservative medical management. REFERENCES
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