Interstitial Cystitis Update*
Author: Since this paper has been edited by Dr. Newman, the name of the author has been removed....pending the granting of permissions
Introduction, Etiology, Diagnosis, Treatment
To Veterinary Folder
Abstract: Interstitial cystitis (IC) likely results from multiple etiologies. The diagnosis can be applied to a broader range of patients than those who meet the research definition of National Institute of Diabetes and Digestive and Kidney Diseases. Recent evidence makes a stronger case for an autoimmune cause than previously. Bacteria undetected by routine urine culture may also contribute to the pathogenesis of IC. Although treatment remains empiric, a variety of oral and intravesical therapies are available. Patients with a bladder capacity of less than 250cc may benefit from surgery. [The Original Version is in: Infect Urol 10(3):75-79,80, 1997. © 1997 SCP Communications, Inc.]
The syndrome known as interstitial cystitis (IC) remains an enigma. Of the almost 500,000 people in the US who have symptoms suggestive of IC, 90% are women. The primary symptoms are chronic urinary frequency associated with urethral, pelvic, and/or bladder pain, and often dyspareunia. The etiology of IC is likely from a variety of causes, and the syndrome may represent a common pathologic endpoint for several disease process
The etiology and pathogenesis of IC are unknown. Among the many theories proposed for the etiology are: (1) autoimmune disease, (2) infection, (3) bladder ischemia, (4) presence of toxic substances in the urine, and (5) a defect in the protective glycosaminoglycan (GAG) layer of the bladder. This defect could lead to the absorption of potentially toxic substances across the bladder epithelium and set up a chronic inflammatory reaction in the subepithelial layers or expose the bladder to uncommon antigens, leading to an immune response. None of these theories has been definitively shown to be the cause of IC, but most of the newer information about the etiology involves the autoimmune disease and infection theories which are, therefore, the focus of our discussion.
Autoimmune theory. Recent findings have supported the theory that IC is an autoimmune phenomenon. The major antibody detected thus far in the sera of patients with IC is characterized by a dense, fine-speckled nuclear immunofluorescence pattern and a 70 kDa protein identified by Western blot. Patients with this antinuclear antibody (ANA) staining pattern comprise up to 25% of all IC patients tested to date, indicating that this 70 kDa protein may be a major autoantigen. Ochs also found this pattern in randomly selected ANA-positive patients referred from rheumatology. None of these patients had a diagnosis of IC, but 55% were diagnosed with fibromyalgia/fibrositis or arthralgia/myalgia. The predominant symptoms occurring in over half of these patients were a debilitating fatigue and multisite pain. The finding of this autoantigen in both urology and rheumatology patients raises the question of whether IC is part of a spectrum of diseases characterized by antibodies to the 70 kDa autoantigen, which manifest with pain and fatigue, rather than the "classic" rheumatology-related symptoms of systemic autoimmune diseases such as lupus or scleroderma.
Studies by Clauw and colleagues further support the autoimmune disease theory. These investigators compared a group of 20 patients with IC to 60 patients with fibromyalgia. Both groups of patients showed frequent occurrence of musculoskeletal symptoms, including myalgias and morning stiffness. The rates of occurrence of symptoms not referable to the urinary tract or musculoskeletal system were relatively equal in both groups, including migraine, paresthesias, and fatigue. The investigators concluded that IC may have some clinical overlap (perhaps pathophysiologically) with fibromyalgia.
Gordon and associates reported on a series of patients (n=16) who complained of joint and muscle pain and severe fatigue. Ten of 15 patients had elevated levels of antithyroid globulin or antimicrosomal antibodies, and 12 of 16 had dry eyes and/or dry mouth. Specific urinary symptoms were not given (all had IC). Results of Schirmer's test were abnormal in 5 of 8 tested. These data also suggest that IC may be 1 manifestation of a generalized systemic autoimmune process. Clinically, it may be helpful to screen IC patients for other abnormalities that may require rheumatologic evaluation.
Prostatodynia. Another condition possibly closely related to IC is prostatodynia. This term refers to men with symptoms of prostatitis, including prostatic or pelvic pain and discomfort, but no documented urinary tract infection nor evidence of inflammation or infection in the expressed prostatic secretions (EPS). Patients who have inflammation seen on microscopy of the EPS but no culture-documented infection are classified as having nonbacterial prostatitis.
Miller and coworkers found petechial hemorrhages (glomerulations) of the bladder epithelium after hydrodistension in 12 of 20 patients with prostatodynia or nonbacterial prostatitis. All patients had a chief complaint of genital or rectal pain or both. Nine of the 12 patients with glomerulations had symptomatic improvement following hydrodistension versus none of the patients without glomerulations. These findings suggest that a diagnosis of IC should be considered in men with nonbacterial prostatitis or prostatodynia.
Infection. A history of UTI is twice as common among patients with IC as it is in controls. However, to date, studies attempting to document a pathogenic organism in IC have been inconclusive. Keay and associates cultured urine and bladder tissue from IC patients and controls for a variety of fastidious organisms. Urine cultures from 6 of 11 IC patients grew 5 different species of bacteria. No bacteria grew in the urine of any of the control patients. Although these data did not provide evidence that IC is associated with infection or colonization by a single microorganism, they do suggest that the prevalence of bacteria, especially at low concentrations, is greater in IC patients than in controls. These organisms could be affecting the bladder, even at low concentrations.
Certain bacterial constituents, even in the absence of the whole organism, can elicit inflammation. Lipopolysaccharide (an endotoxin) and P fimbriae can cause bladder inflammation after instillation into the bladder; together the 2 produce a greater degree of inflammation than either component alone. Bjorling and Saban found that the bacterial products hemolysin and lipopolysaccharide can induce the release of cytokines such as tumor necrosis factor-alpha (TNF-alpha), gamma-interferon (gamma-IFN), and transforming growth factor-beta (TGF-beta) from the mouse bladder. Lipopolysaccharide also augmented substance-P-induced cytokine release from the mouse bladder.
Domingue and associates also have contributed to the concept that IC is an infection not detectable by routine cultures. This investigator used polymerase chain reaction (PCR) to amplify a common shared gene in bacteria, 16S rRNA. In bladder biopsies of 22 patients with IC, 29% had 16S rRNA. No control had the gene. Cloning and sequencing of gene fragments amplified from bladder tissue of IC patients showed that these genes were derived from gram-negative bacteria. Yet none of the IC patients had growth of bacteria on routine cultures. PCR also detected the presence of a filterable 0.22-micron organism in the bladder tissue of 14 out of 14 IC patients and 1 out of 15 controls. The organism contained nucleic acids and resembled cell-wall deficient bacteria in gross morphology. Electron microscopy demonstrated a swirled myelin-like pattern that has yet to be classified. Neither the significance of this finding nor the characterization of this organism has been determined.
NIDDK criteria. IC is a diagnosis of exclusion and thus has been difficult to characterize for research studies. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has developed consensus criteria for the diagnosis of IC. In order to confirm the diagnosis, a cystoscopic examination is performed under anesthesia after distension of the bladder to 80-100cm of water pressure for at least 1 to 2 minutes. Patients must have either diffuse glomerulations on cystoscopic examination (Fig. 1) or a classic Hunner's ulcer (Fig. 2), seen in less than 10% of patients. Clinically, the patient must have either pain associated with the bladder or urinary urgency.
Figure 1. Cystoscopy shows diffuse glomerulations after bladder distension to 80-100cm water pressure for at least 1-2 minutes. Reprinted with (in the original publication) permission from Campbell's Urology Update (#14; 1995), Copyright © 1995 W.B. Saunders Company.
These NIDDK criteria were not meant to define the disease, but to create a research definition to ensure that all groups of patients treated would be relatively comparable. However, these guidelines have become the de facto definition of the condition. Yet there are still patients considered clinically to have IC who do not fulfill all the criteria established by the NIDDK.
Differential diagnosis. The hallmarks of IC--bladder pain, urgency, frequency, nocturia, and dysuria--are not only found in patients with IC. Thus, an important part of the diagnostic evaluation is to exclude other neoplastic, infectious, and inflammatory processes that can produce these symptoms, including bladder carcinoma and carcinoma in situ, bacterial cystitis, tuberculosis, radiation cystitis, cyclophosphamide cystitis, and malacoplakia. Systemic diseases such as diabetes and multiple sclerosis also can affect the bladder.
Laboratory studies. Laboratory studies should include a urine specimen for urinalysis, culture, and cytology. A bladder biopsy is also performed at the time of hydrodistension, usually postdistension to minimize the risk of bladder perforation (Fig. 3). The biopsy is performed solely to rule out bladder carcinoma, since there are no pathognomonic findings of IC on routine histology. A urodynamics study should be performed to rule out detrusor hyperreflexia, which is amenable to treatment with anticholinergic medication.
Figure 2. (click here to zoom image) Cystoscopy shows Hunner's ulcer. Reprinted with permission (in the original publication) from Campbell's Urology Update (#14; 1995), Copyright © 1995 W.B. Saunders Company.
Other conditions not meeting NIDDK criteria. Awad and associates coined the term "idiopathic reduced bladder storage" to describe a group of patients with irritative symptoms similar to IC but without the typical cystoscopic findings. In a comparison between a group of 19 patients with idiopathic reduced bladder storage and 42 patients with a diagnosis of IC, the 2 groups were found to have similar irritative symptoms, suprapubic pain, histologic appearance of bladder biopsies, and response to hydrodistension and anticholinergic medication. The only significant difference was the lack of glomerulations after hydrodistension.
Similar findings were reported by Felsen and colleagues, who studied patients with a history of and symptoms consistent with IC. Patients were divided into those meeting NIDDK criteria (group A) and others who did not meet all criteria (group B). The 2 groups of patients had similar bladder capacities. Group A patients had glomerulations on cystoscopy, and those in group B did not. Functional capacity, therefore, does not predict glomerulations. Both groups had a smaller capacity under anesthesia than did controls. However, both groups had a mean bladder anesthesia capacity of 740mL, clearly not low bladder capacity. Thus, many patients with IC have bladder capacity nearly equal to that of patients without IC, as defined by the NIDDK criteria.
Hydrodistension. Because the etiology of IC is unknown, treatment cannot be directed at the cause. Therapy is targeted at symptomatic relief or at 1 of the possible causes, such as a deficient GAG layer. Hydrodistension, in addition to being diagnostic, is also usually the initial therapy for IC. Hanno and Wein reported on the results of hydrodistension in 124 patients who met NIDDK criteria for IC. Hydrodistension for 8 minutes at 80cm H20 successfully achieved temporary relief of pain in 28% of patients with a bladder capacity of less than 600mL under anesthesia. Only 14% of patients with a capacity over 600mL had relief of symptoms. Approximately the same number of patients experienced exacerbation of pain after distension; 45% in both groups rated their response to hydrodistension as poor. Responses were brief and rarely lasted 6 months. We usually wait approximately 2 weeks after hydrodistension to see if there is a response. If no response occurs, other therapy is started.
Oral drugs. First-line therapy after hydrodistension includes the tricyclic antidepressant amitriptyline. Tricyclic antidepressant mode of action includes central and peripheral anticholinergic activity at some, but not all, sites; blockade of the active transport system in the presynaptic nerve ending that is responsible for the re-uptake of the released amine neurotransmitters serotonin and norepinephrine; and anti-H1 antihistamine properties, which have been shown to contribute to stabilization of mast cells in vitro and which may also produce some sedation via a centrally acting mechanism. The dosage is started at 25mg qhs and increased to up to 75mg qhs over 3 weeks. More than 50% of patients had relief of symptoms for more than 1 year, and none experienced tachyphylaxis.
Another oral medication that can be used after amitriptyline has been unsuccessfully tried is hydroxyzine at 50mg to 75mg daily. Hydroxyzine is an antihistamine that can block the neuronal activation of mast cells. In a series of 40 patients treated with 25mg in the morning and 25mg to 50mg at bedtime, improvement was achieved in 30% of patients for almost all symptoms.
Nifedipine also has been reported to be useful in treating IC. Fleischmann and colleagues performed an open trial of nifedipine therapy in 10 IC patients. Based on the reduction of symptom score, 8 of 9 patients had a substantial clinical response for a duration of at least 4 months, and 3 became asymptomatic. Calcium channel blockers cause vasodilation, and nifedipine may act in IC by increasing bladder blood flow. Nifedipine has also been reported to inhibit detrusor contractions and depress cell-mediated immune function. Hypotension is a possible side effect, and patients should be monitored at the beginning of therapy.
Intravesical therapy. For patients who do not respond to oral therapy, intravesical therapy can be used. The initial intravesical therapy should be dimethylsulfoxide (DMSO). The efficacy of DMSO is likely due to its action as an anti-inflammatory, analgesic, muscle relaxant, mast cell inhibitor, and facilitator of collagen dissolution. Overall satisfactory response to DMSO ranges from 53% to 90% in patients with follow-up of 6-24 months. The medication is administered via a urethral catheter weekly for 6 weeks, after which the patient is reassessed for a therapeutic response. Patients who have a positive response may use monthly maintenance instillations.
For refractory patients, intravesical sodium oxychlorosene (Chlorpactin) can be tried. Chlorpactin was originally used to treat tuberculosis of the bladder because of its antimicrobial activity. It must be administered by gravity drip (10cm pressure) under anesthesia because it inflicts a great deal of pain when instilled into the bladder. If no response is seen after the first instillation, a second treatment can be tried in 1 month. In a study reported by Sant and LaRock, 50% to 60% of patients had an improvement of symptoms. Because of reported ureteral fibrosis after instillation, patients with ureteral orifices that appear incompetent on cystoscopic examination should have a cystogram prior to instillation to rule out vesicoureteral reflux.
The rare patient with a Hunner's ulcer may benefit from transurethral fulguration, laser irradiation, or transurethral resection of the isolated ulcer. Laser treatment should be used with caution, however, as the bladder in IC can be very thin, and forward scatter of laser energy can cause damage to the bowel.
Other agents. Parsons and others suggested that a defect in the epithelial permeability barrier, the GAG layer, contributes to the pathogenesis of IC. In an attempt to correct such a defect, a synthetic sulfated polysaccharide, in oral form, that is excreted in the urine has been used in clinical trials. Sodium pentosan-polysulfate (Elmiron) consists of a negatively charged polysaccharide ester (a polyanion) with properties of sulfated glycosaminoglycans and an affinity for mucosal membranes. A 3-month, randomized, prospective, double-blind, placebo-controlled, multicenter study of 148 patients (74 in each group) reported that 32% of the patients receiving the drug showed a greater than 50% improvement in symptoms, compared with 16% of those receiving placebo (P=0.01). Elmiron is now available for use.
Narcotics. The use of long-term opioid therapy in patients who have failed all forms of conservative therapy over many years should be considered. Opioids are effective for most forms of moderate and severe pain. Common side effects include sedation, nausea, mild confusion, and pruritus. Respiratory depression is uncommon and rare if prescribed doses are used. Constipation can occur and is usually corrected with a laxative. The major reason for not using this class of drugs is the fear of addiction. The long-acting narcotic formulations that provide steady serum levels of drug over many hours are preferable to shorter-acting analgesics. Chronic opioid therapy can be considered as a last resort in selected patients with IC. It is best administered in a pain clinic setting and requires frequent assessment by both patient and physician.
Surgery. Because there is a spontaneous remission rate of approximately 20%, based on the rate of response to placebo in clinical trials, all conservative measures should be exhausted before surgical therapy is attempted. Substitution cystoplasty with resection of the bladder to the trigone and the anastomosis of the detubularized bowel segment to the trigonal remnant can be performed in patients with small bladder capacity as measured under anesthesia. Webster and Maggio reported resolution of pain in 12 of 19 patients undergoing supratrigonal substitution cystoplasty; 4 of the remaining 7 patients reported an improvement. A bladder capacity of less than 350mL under anesthesia correlated with success. These results were further supported by Hughes and associates, who reported that after cystoplasty, 20 of 22 patients with a bladder capacity of less than 250mL (small capacity) under anesthesia were either cured (15 patients) or showed improvement of symptoms (5 patients). In 7 patients with a larger-capacity bladder, only 2 patients were cured. The investigators found that performing a supratrigonal cystectomy increased the chance of voiding without the need for clean intermittent catheterization after the procedure, but also increased the risk of reflux and pyelonephritis.
There are some disadvantages of substitution cystoplasty compared with diversion. In patients who cannot adequately empty their bladder after a cystoplasty, intermittent catheterization may become necessary. This can be a painful experience for a patient with IC who may have a hypersensitive urethra and trigone. There also may be involvement of the residual bladder tissue. In performing a diversion, the bladder may be left in situ because there is no malignant process. However, the retained, nonfunctioning bladder also may develop pyocystis.
An alternative surgical procedure may be cystectomy and creation of a neobladder from bowel segments. Bejany and Politano performed a cystectomy, leaving the urethra in place, in 5 women with IC and created an ileocolonic neobladder which was attached to the urethra. Two women needed clean intermittent catheterization to empty the bladder, but 3 voided to completion. At follow-up of a mean of 52 months, all women were symptom-free. All 5 patients had a preoperative bladder capacity under anesthesia of less than 250cc.
Investigational therapies. Some previously promising therapies such as intravesical BCG have not been as effective in follow-up trials. Other newer intravesical therapies such as a combination of bupivacaine, heparin, steroids, and gentamicin have had early success.
One of the most interesting therapies for IC may be the use of intensive antibiotictherapy. Although routine short courses of standard antibiotics generally have been unsuccessful in treating IC, the efficacy of longer courses of antibiotics, analogous to treating chronic prostatitis, is not known. Ghoneim and associates gave IC patients 1 month of ciprofloxacin 500mg PO bid along with rifampin 600mg/day starting on week 2 and continuing for 3 weeks. Of 6 patients on this regimen, all demonstrated gradual improvement of symptoms from the second to the fourth week. Two patients had a relapse of pain after a temporary improvement of 1-2 months. Another patient had a partial improvement requiring less need for DMSO instillations, and 3 patients demonstrated a durable cure of their symptoms for more than 1 year. Although these results are promising, the routine use of prolonged courses of antibiotics is not recommended since the most appropriate antimicrobial agents and duration of treatment remain to be determined.
L-arginine has been reported to be useful in treating IC. Smith and colleagues found that nitric oxide synthase (NOS) activity in the urine pellet of women with IC is decreased compared with non-IC patients or patients with an acute UTI. L-arginine is the substrate for NOS to produce nitric oxide. Patients were given 1.5-3.0g/day of L-arginine orally. After 1 month of treatment, symptoms improved in 7 of 8 patients. NOS activity in the urine pellet also increased over this time period.
Although the cause of IC remains elusive, an intensive research effort is under way through initiatives by the NIDDK in conjunction with the Interstitial Cystitis Association. Areas of interest include the role of the bladder epithelium in IC. Bladder epithelial cells can respond to immune stimulation by the production of cytokines and the expression of an activated cell-surface phenotype. Efforts to define the role and physiology of the bladder epithelium will be aided by the successful culture of bladder epithelium cells from patients with IC.
Another advancement in the study of this condition is the establishment of an IC Database. A multicenter group is collecting information on IC patients in an attempt to better classify and understand this condition. Early reports, including a comparison of urodynamic and cystoscopic findings, are being made available.
It is hoped that, through continued research efforts, including coordinated projects such as the IC database and ongoing trials of new treatments, progress can be made toward a rational and successful therapy for interstitial cystitis.
Interstitial Cystitis: A brochure provided by the National Institute of Diabetes and Digestive and Kidney Disease of the National Institutes of Health (NIH). Contains information on the causes, diagnosis, and treatment of interstitial cystitis as well as information on current research studies that aim to understand and treat the disorder. Interstitial Cystitis: Progress Against Disabling Bladder Condition. An article from the November 1995 issue of FDA Consumer, the magazine of the U.S. FDA.
*VETERINARIANS Please Note: This paper was originally downloaded with permission from MedScape then rather drastically reformatted for this web site. Since the material has been edited without permission of both the original authors, and the publisher, the latter can not be held liable for the information contained herein. Dr. Newman is currently attempting to obtain permissions and legitimize the publication of this particular altered reproduction.