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PubMed2001

Observations on the presentation, diagnosis, and treatment of interstitial cystitis in men.

This article presents and evaluates the symptoms, presentation, diagnosis, and treatment of men with interstitial cystitis (IC). A retrospective chart review and an interview of all men in our practice diagnosed with IC since 1990 was performed. The patients' presenting symptoms, physical findings, clinical evaluation, and responses to therapy were reviewed. A total of 52 men were identified during the study who met the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria for diagnosis of IC. The most common referral diagnosis was prostatitis with the most common predominant symptoms being suprapubic pain with urinary frequency and dysuria. A significant number of male patients also developed sexual dysfunction. All patients met the NIDDK criteria for a diagnosis of IC. Multiple therapies were used for the treatment of these patients over the study period. Five patients were initially treated with dimethyl sulfoxide (DMSO) as a sole agent; however, all intravesically treated patients eventually failed this form of therapy. A total of 37 of 52 patients were treated with multidrug oral therapy. Findings showed that 80% of patients achieved >75% improvement in their symptomology at 6 months of follow-up with a durable response at 1 year. IC in men is probably underdiagnosed and is most commonly misdiagnosed as prostatitis. The patient's presentation is analogous to that in the female population allowing for gender differences. The patients responded well to multidrug oral therapy.

Adult↗
PubMed2001

Interstitial cystitis: a chronic visceral pain syndrome.

Interstitial cystitis (IC) has remained an unresolved problem in clinical urology. The etiology and pathophysiologic mechanisms of IC are still undetermined, and to date the diagnosis is based on the clinical characteristics of the disease and the exclusion of other diseases and pathology that can mimic the symptoms of IC. In clinical practice, much emphasis has been placed on finding a specific etiology and specific pathologic markers for the disease and on identifying specific events that precipitate IC; however, those have not been identified with certainty. In this review, an additional approach is proposed, taking into account the observation that IC shares many features with other chronic nonmalignant visceral pain syndromes. This approach is based on the conceptualization of 3 hypotheses: (1) a spectrum of different insults can lead to chronic visceral pain in patients with IC; (2) different underlying pathogenic pain mechanisms may require different pain treatment strategies for patients diagnosed with IC; and (3) multiple different pathogenic pain mechanisms may coexist in the same patient requiring several different pain treatment strategies (perhaps concomitantly) to successfully treat chronic visceral pain associated with IC. This concept is likely to lead to new insights into the pathophysiologic mechanisms of IC and to novel treatment avenues for patients with IC and-in a broader view-also for patients with other chronic visceral pain syndromes.

Chronic Disease↗
PubMed2001

Urine markers of interstitial cystitis.

This article describes the current state of the art with regard to urine markers of interstitial cystitis (IC), and describes the areas that need continuing research. Articles referenced in MEDLINE that describe urine alterations in IC were reviewed. Additional articles were identified by cross-referencing. The different marker alterations were tabulated. The relevant articles were discussed, considering different purposes for urine markers including: (1) diagnosing IC; (2) confirming a specific pathophysiology for IC; and (3) predicting or following response to a specific treatment. Currently, 2 markers (glycoprotein-51 and antiproliferative factor [APF]) clearly separate IC and control subjects, with minimal overlap. Markers that correlate with specific bladder biopsy features include 1,4-methylimidazole acetic acid and eosinophil cationic protein (ECP), which correlate with mast cell density, and interleukin (IL)-6, which correlates with mononuclear inflammation. Markers that changed after treatment were as follows: (1) nitric oxide synthase and cyclic guanosine monophosphate increased with oral L-arginine; (2) ECP decreased with subcutaneous heparin; (3) prostaglandin E(2) and kallikrein decreased after bladder distention; (4) neutrophil chemotactic activity decreased after dimethyl sulfoxide; (5) IL-2 inhibitor decreased after oral nifedipine; (6) IL-2, IL-6, and IL-8 decreased after bacille Calmette-Guérin (BCG) vaccine; and (7) APF and heparin-binding epidermal growth factor changed to or toward normal levels after bladder distention or sacral nerve stimulation. A larger number of urine alterations have been reported, and a few are being pursued further by correlating with bladder biopsy findings or treatment responses. Further research is needed.

Biomarkers↗
PubMed2001

Mast cell involvement in interstitial cystitis: a review of human and experimental evidence.

Interstitial cystitis (IC) is a heterogeneous syndrome of unknown etiology. Altered bladder glycosaminoglycans lining and bladder mastocytosis have been documented in IC. The objective of this article is to critically examine the published data on bladder mastocytosis in clinical, experimental, and animal studies, with particular emphasis on morphologic evidence of mast cell increase and activation. The literature on bladder mastocytosis and mast cell activation in IC is critically reviewed with particular reference to staining methodology, tryptase immunoreactivity, and electron microscopy. Data from humans and animal models of IC are included. Mastocytosis in IC is best documented by tryptase immunocytochemical staining. Standard surgical stains such as Giemsa and toluidine blue routinely underestimate the degree of mastocytosis. Mast cells are 6- to 8-fold higher in the detrusor compared with controls in "classic IC," and 2- to 3-fold higher in "nonulcerative" IC. Detrusor mastocytosis occurs in both classic and nonulcer IC. Mucosal mast cell increase is present in nonulcerative IC. Mast cell activation without typical exocytosis occurs in the mucosa and submucosa. Activation of mast cells, irrespective of bladder location or degree of mastocytosis, is significant. Mast cell-derived vasoactive and proinflammatory molecules may contribute to the pathogenesis of IC.

Animals↗
PubMed2001

Interstitial cystitis: current issues and controversies in diagnosis.

Current tests for the diagnosis of interstitial cystitis (IC) are reviewed, including clinical assessment, urodynamic testing, cystoscopy, bladder biopsy, and urinary markers. A MEDLINE search was performed of all studies dealing with the diagnosis of IC. These studies were critically reviewed with the goal of arriving at a utilitarian approach to IC diagnosis. IC is being diagnosed with increasing frequency. However, the diagnostic criteria are nonuniform and there is significant overlap between chronic pelvic pain syndromes in men and women and IC. Diagnosis of IC can be made clinically and by cystoscopy and hydrodistention. The sensitivity and specificity of urinary markers have not been prospectively studied. Individual practitioners continue to use the various diagnostic tests. There is a clear need for uniform diagnostic criteria for clinical diagnosis as well as epidemiologic and research studies.

Biomarkers↗
PubMed2001

A case of familial clustering of interstitial cystitis and chronic pelvic pain syndrome.

A case of familial clustering of interstitial cystitis (IC) and chronic pelvic pain syndrome (CPPS), a symptom complex similar to IC that occurs in men, is reported. The proband was a 28-year-old woman with a 6-month history of severe frequency, urgency, and genital pain. After cystoscopy with hydrodistention and biopsy, a diagnosis of IC was made. IC was also diagnosed in the patient's mother and in two of her brothers, previously considered to have CPPS (category IIIB CPPS). A third brother was asymptomatic. This case highlights the importance of genetic factors in the onset of symptoms and natural history of IC and CPPS.

Adult↗
PubMed2001

The epidemiology of interstitial cystitis: is it time to expand our definition?

Very few epidemiologic studies of interstitial cystitis (IC) have been published over the past 5 years. One population-based study focused only on women and suggested that the prevalence of the IC symptom complex in the United States is much higher than previously reported. Future epidemiologic studies of IC must overcome major obstacles to obtain more accurate population-based estimates. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria used to assist in identifying patients with IC have proven to be cumbersome and too restrictive. Other obstacles include (1) the relative infrequency of the condition; (2) the long duration between development of symptoms and diagnosis; and (3) the perception that the disorder occurs predominantly in white women. Evidence suggests men with the IC symptom complex are often misdiagnosed by physicians and identified as having chronic prostatitis (also called the chronic pelvic pain syndrome) or benign prostatic hyperplasia. Children who present with the IC symptom complex are often thought to have voiding dysfunction. We propose that the more inclusive, less restrictive term chronic pelvic pain of the bladder (CPPB) be used in future epidemiologic studies of persons with the characteristic IC symptoms of urinary frequency, urgency, and pain. Early studies of chronic pelvic pain in general suggest that it is most common in women, of unknown etiology, and, in many patients, is associated with urinary bladder symptoms. It is necessary to develop case definitions for CPPB to accurately identify those patients with symptoms currently identified as IC.

Cystitis, Interstitial↗
PubMed2002

Leukocyte populations in interstitial cystitis and idiopathic reduced bladder storage.

OBJECTIVES: Mast cells and leukocyte populations in bladder biopsies from women with interstitial cystitis (IC) or idiopathic reduced bladder storage (sensory urgency [SU]) were compared to determine whether any evidence of a common etiology between these conditions could be found. METHODS: Biopsies from 40 patients (9 meeting the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases criteria [IC] and 31 who did not [SU]) and 20 controls (having colposuspension for stress incontinence) were stained with monoclonal antibodies against leukocyte antigens and mast cell tryptase. The median cell counts from 10 high power fields were calculated and compared between cases and controls. The clinical and urodynamic data were also compared. RESULTS: Nocturia (odds ratio 26.7; 95% confidence interval 3.3 to 245.5) and bladder pain (odds ratio 18.5; 95% confidence interval 1.8 to 193.1) were associated with significant odds ratios for disease (IC or SU compared with controls) in logistic regression analysis. Patients with IC were significantly older than those with SU (P = 0.05). Leukocyte populations showed only increased CD20+ cells in patients with IC compared with the others (P = 0.03). CONCLUSIONS: The analysis of the clinical, urodynamic, and cystoscopic data showed no differences between patients with IC and those with SU, except for age. Nocturia or bladder pain discriminated between patients and controls. The lymphocytic infiltrate in SU is similar to that seen in IC but with fewer CD20+ cells. These data support the work of others and may indicate that SU has a common etiology with IC.

Case-Control Studies↗
PubMed2002

Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity.

OBJECTIVES: Most individuals with interstitial cystitis (IC) have both pelvic pain and urinary urgency/frequency, and many have dyspareunia. Existing questionnaires designed to assess bladder-origin pelvic pain (IC) give little attention to pelvic pain or dyspareunia, however. On the basis of our clinical experience with more than 5000 patients with IC, we have designed a pelvic pain and urgency/frequency (PUF) symptom scale that gives balanced attention to urinary urgency/frequency, pelvic pain, and symptoms associated with sexual intercourse. METHODS: We used the intravesical potassium sensitivity test (PST) to validate the PUF scale in urologic patients suspected of having IC, gynecologic patients with pelvic pain, controls, and women attending lectures given by one of us (C.L.P.). Positive potassium sensitivity is known to be associated with a bladder epithelial dysfunction present in most individuals with IC. RESULTS: The PST was positive in 74% of patients with a PUF score of 10 to 14, 76% of those scoring 15 to 19, and 91% of those scoring 20 or higher. All controls' PUF scores were less than 3, and the rate of positive PST in controls was 0%. The PUF scores in women screened at lectures suggested that 1 in 4.5 women have IC. CONCLUSIONS: High PUF scores appear to correlate directly with a higher likelihood of positive PST in both urologic patients suspected of having IC and gynecologic patients with pelvic pain. The PUF appears to be a valid tool for detecting IC in these two populations, as well as in the general population. Use of the PUF alone may prove to be an accurate method for detecting IC. The IC prevalence may be as high as 1 in 4.5 women.

Administration, Intravesical↗
PubMed2003

Comparison of APF activity and epithelial growth factor levels in urine from Chinese, African-American, and white American patients with interstitial cystitis.

OBJECTIVES: Interstitial cystitis (IC) is a chronic bladder disorder for which the etiology is unknown. We have previously shown that antiproliferative factor (APF), heparin-binding epidermal growth factor-like growth factor (HB-EGF), and epidermal growth factor (EGF) are sensitive and specific biomarkers for IC in white American patients. Because little is known about the epidemiology of this disorder, it is unclear whether these factors would also be useful biomarkers for IC in patients from different racial groups and/or geographic locations. METHODS: Urine specimens were collected from Chinese, white American, and African-American women with IC and age and race-matched asymptomatic normal control women. APF activity was determined by (3)H-thymidine incorporation into primary normal adult human bladder epithelial cells in vitro. The HB-EGF and EGF urine levels were determined by enzyme-linked immunosorbent assay. RESULTS: The Chinese, African-American, and white American women with IC had significantly greater urine APF activity (P <0.000001, P = 0.0008, and P <0.000001, respectively), lower urine HB-EGF levels (P <0.000001, P = 0.02, and P <0.000001, respectively), and greater urine EGF levels (P <0.000001, P = 0.002, and P <0.000001, respectively), than their matched asymptomatic controls. CONCLUSIONS: These findings confirm the utility of APF, HB-EGF, and EGF as biomarkers for IC in patients from three different racial groups and two different countries.

Adult↗
PubMed2003

Decreased in vitro proliferation of bladder epithelial cells from patients with interstitial cystitis.

OBJECTIVES: To determine whether explanted bladder epithelial cells from patients with interstitial cystitis (IC) display intrinsically decreased rates of proliferation in vitro, and to compare the growth rates of untreated IC and normal bladder cells with the rates of normal cells treated with a purified antiproliferative factor (APF) at levels found in urine from patients with IC. METHODS: Epithelial cell explants were prepared from the bladder biopsies of 4 patients with IC and 2 asymptomatic controls. Cell proliferation was determined by serial counting of trypan blue-negative cells. APF and mock APF were purified chromatographically, and activity was determined by (3)H-thymidine incorporation into primary normal bladder epithelial cells. Heparin-binding epidermal growth factor-like growth factor and epidermal growth factor were measured by enzyme-linked immunosorbent assay. RESULTS: Bladder epithelial cells from patients with IC proliferated significantly less than did control cells by day 2 after serum starvation (P = 0.02). Similar inhibition of the proliferation rate was seen in control cells treated with APF; APF-induced changes in heparin-binding epidermal growth factor-like growth factor, but not epidermal growth factor, production by cells were associated with changes in growth rates. CONCLUSIONS: The proliferation rate of explanted bladder epithelial cells from patients with IC in serum-free medium was significantly less than that of control cells, indicating an intrinsic abnormality in IC cell proliferation. This abnormality may be caused by APF, which induces reversible inhibition of heparin-binding epidermal growth factor-like growth factor production and normal bladder epithelial cell proliferation.

Adult↗
PubMed1994

Cimetidine in the treatment of interstitial cystitis.

OBJECTIVES: To assess the effect of the H2-antagonist cimetidine in the treatment of patients with interstitial cystitis (IC) refractory to other conservative therapies. METHODS: A group of 9 patients previously treated conservatively for IC without success were entered in the study. They were thoroughly investigated and treated with cimetidine at the dose of 300 mg orally twice a day for 1 month. RESULTS: Six of the 9 patients (66%) experienced various degrees of symptomatic relief while on the drug. Of these, 4 (44%) have noted a complete and sustained response to the medication. CONCLUSIONS: The encouraging results observed in this pilot study together with the simplicity and tolerance of the treatment makes it an alternative when other options have been exhausted. Its use as a first-line monotherapy remains speculative.

Administration, Oral↗
PubMed1994

Relationships between bladder inflammation and other clinical features in interstitial cystitis.

OBJECTIVES: Interstitial cystitis (IC) has been considered possibly to represent more than one disease process. If so, patients would be expected to form distinct subgroups. The degree of mononuclear inflammation on bladder biopsy can be objectively quantified and might be a useful parameter for subgroup division. The hypothesis of this study was that patients with mild versus severe inflammation would differ with regard to other clinical features of IC. METHODS: Sixteen patients who met the original National Institute of Diabetes, Digestive and Kidney Diseases criteria for IC underwent cystoscopy with bladder distention and biopsy. The degree of mononuclear inflammation on bladder biopsy was classified as mild, with less than 100 mononuclear cells/high power field (HPF), or severe (100 or more mononuclear cells/HPF or lymphoid aggregates). Associations were sought between degree of inflammation and other subjective and objective clinical features. RESULTS: Five patients had severe inflammation and 11 had mild inflammation. The major finding was that the patients with severe inflammation experienced better symptom relief after cystoscopy with bladder distention under anesthesia. This difference was highly significant (Fisher's exact test, p = 0.0014). For the other clinical features studied, these two groups did not differ significantly. CONCLUSIONS: Two distinct IC patient groups were identified by bladder biopsy findings. These two groups had significantly different treatment responses. If this difference is confirmed with a larger number of patients, it would suggest that these two patient groups may have different underlying disease processes.

Adult↗
PubMed1995

Resolution time of Escherichia coli cystitis is correlated with levels of preinfection antibody to the infecting Escherichia coli strain.

OBJECTIVES: A number of studies in animals have demonstrated that immunization against uropathogenic bacteria can lessen the severity or duration of induced urinary tract infections (UTI). This study examined whether preinfection levels of serum or urinary anti-Escherichia coli antibodies were correlated with length of time needed to resolve an induced E coli cystitis. METHODS: Serum and urine anti-E coli antibody levels in 36 control and 42 vaginally immunized cynomolgus monkeys were measured by enzyme-linked immunosorbent assay. Regression analyses were used to determine correlations between resolution time and preinfection antibody level, and to estimate antibody levels that might be associated with effective resolution of an E coli UTI. RESULTS: Linear regression analysis showed significant correlations between short resolution time and high levels of serum immunoglobulin M (IgM), urinary secretory IgA, and urinary IgG specific for the infecting E coli strain. Serum IgM and urinary IgG anti-E coli levels in monkeys that cleared infections early were significantly higher than in animals with protracted infections. Logistic regression estimated the serum IgM and urinary IgG anti-E coli levels associated with a 50% probability of accelerated clearance to be 3.3 micrograms/mL and 2.7 micrograms/24 hours, respectively. CONCLUSIONS: For this primate model, the observed correlations between short resolution time and pre-existing serum and urinary antibody suggest that antibody-mediated immunity is an important component of host defense against UTI.

Animals↗
PubMed1996

Carbachol-induced bladder mast cell activation: augmentation by estradiol and implications for interstitial cystitis.

OBJECTIVES: Interstitial cystitis (IC) is a painful, sterile bladder disorder that occurs primarily in women, many of whom also experience allergies with symptoms that worsen perimenstrually. Increased numbers of activated bladder mast cells have recently been implicated in the pathophysiology of IC. These mast cells express high-affinity estrogen receptors and are located close to increased bladder nerves, many of which contain the neuropeptide substance P (SP). We therefore investigated whether the neurotransmitter acetylcholine (ACh) and SP could activate bladder mast cells and whether estradiol could influence this effect. METHODS: Bladder pieces from male Sprague-Dawley rats were perfused with carbachol (the stable analogue of ACh), SP, or the mast cell secretagogue compound 48/80 (C48/80) with or without preincubation with beta-estradiol. The effect of carbachol was also investigated after pretreatment with the muscarinic antagonist atropine. Mast cell activation was assessed by release of 3H-serotonin and morphologic evidence of secretion by light and electron microscopy. RESULTS: Carbachol triggered rat bladder mast cell serotonin release in a dose-dependent manner, an effect increased by tissue pretreatment with estradiol and blocked by atropine. The effect of carbachol was accompanied by ultrastructural evidence of mast cell activation and was stronger than that obtained by either C48/ 80 or SP. CONCLUSIONS: Bladder mast cell activation is neurogenically mediated and augmented by estradiol, findings that could possibly explain the painful symptoms of IC and its prevalence in women, as well as the worsening of symptoms perimenstrually.

Acetylcholine↗
PubMed1996

A deficit of chondroitin sulfate proteoglycans on the bladder uroepithelium in interstitial cystitis.

OBJECTIVES: To investigate the abundance of chondroitin sulfate proteoglycans at the bladder lumenal and subepithelial surfaces in bladder biopsies derived from patients with interstitial cystitis (IC) and controls. METHODS: Tissue sections derived from biopsies from 31 IC patients and 24 pathologically normal control sections were labeled for proteoglycans using the 2B6 anti-"stub" antibody and detected by immunohistochemistry. RESULTS: On the lumenal surface, 5 of 31 (19%) IC sections were positive for proteoglycans versus 14 of 24 (58%) control sections (P = 0.00011). At the basal surface, 5 of 19 IC patients were positive versus 7 of 12 controls (P = 0.032). CONCLUSIONS: A deficit of bladder lumenal and basal proteoglycans is associated with IC. The deficit in basal layer proteoglycans suggests an altered urothelial differentiation program. The lumenal deficit suggests that the charge-dependent exclusion of ions from the bladder surface is compromised in IC.

Chondroitin Sulfates↗
PubMed1997

Hydroxyzine therapy for interstitial cystitis.

OBJECTIVES: To determine the usefulness of oral hydroxyzine for the treatment of symptomatic interstitial cystitis. METHODS: This study was an open-label, nonconsecutive case series of patients treated by their local physicians, in consultation with the authors. A case-report form using visual analog scales was used to assess outcomes. RESULTS: Out of 140 patients, 90 (65%) returned the case-report forms. A 40% reduction in symptom scores was reported. This rose to 55% in patients with a history of allergies. CONCLUSIONS: Hydroxyzine is a useful drug for the symptomatic treatment of IC, especially in patients with documented allergies and/or evidence of bladder mast cell activation.

Cystitis, Interstitial↗
PubMed1997

Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis.

OBJECTIVES: On the assumption that interstitial cystitis (IC) is the result of a defective mucous lining of the bladder epithelium, a study was carried out to investigate the activity of hyaluronic acid (HA) in the treatment of IC. HA is an important glycosaminoglycan (GAG) present in all connective tissues, including the GAG layer of the vesical mucosa. It exhibits a variety of pharmacologic properties that enhance its appeal for the therapy of IC. METHODS: A total of 25 patients, with the characteristic picture of IC and refractory to other medical treatments, participated in a trial of HA. Patients received 40 mg of HA intravesically on a weekly basis for 4 weeks, then monthly. Response to therapy was evaluated by symptom score, voiding diaries, and visual analog scales. RESULTS: An initial positive (complete+partial) response of 56% at week 4 increased to 71% by week 12. This response was maintained until week 20; beyond week 24 there appears to be a moderate decrease in the effectiveness of the medication. There was no significant toxicity attributable to the presence of HA in the bladder. CONCLUSIONS: The response of refractory IC patients to the intravesical administration of HA was gratifying. In the past, many therapies for IC that were initially considered promising failed the test of a controlled study. Further studies will establish the effectiveness of this particular preparation of HA in the treatment of IC.

Administration, Intravesical↗