The role of a leaky epithelium and potassium in the generation of bladder symptoms in interstitial cystitis/overactive bladder, urethral syndrome, prostatitis and gynaecological chronic pelvic pain

The traditional diagnosis of interstitial cystitis (IC) only recognizes the severe form of the disease. The far more common early and intermittent phases of the disease are not perceived to be part of IC but rather are misdiagnosed as urinary tract infection, urethral syndrome, overactive bladder, chronic prostatitis, urethritis, or a type of gynecologic pelvic pain (such as endometriosis, vulvodynia, or some type of vaginitis). All of these patient groups actually suffer from the same bladder disease. This disease results from a leaky bladder epithelium and subsequent potassium leakage into the bladder interstitium that generates the symptoms of frequency, urgency, pain or incontinence in any combination. Robust scientific data now support this important concept. These data will be reviewed herein. The conclusions derived from these data substantially alter the paradigms for urology and gynecology in the generation of frequency, urgency and pelvic pain. All the above-mentioned syndromes unite into one primary disease process, lower urinary dysfunction epithelium, or LUDE disease, and not the 10 plus syndromes traditionally recognized.     

Patients With Chronic Pelvic Pain: Endometriosis or Interstitial Cystitis/Painful Bladder Syndrome?

BACKGROUND: Endometriosis and interstitial cystitis/painful bladder syndrome share similar symptoms. Interstitial cystitis was once considered rare, but it is now recognized as more common than previously thought. This review examines evidence that patients presenting with symptoms typically attributed to endometriosis or with unresolved pelvic pain after treatment for endometriosis may, in fact, have interstitial cystitis, and suggests approaches for appropriate diagnosis. METHODS: A MedLine search using "chronic pelvic pain," "endometriosis," "interstitial cystitis," and "bladder origin pain" as key words was performed for the most recent English-language articles. Additional references were obtained through cross-referencing the bibliography cited in each publication. DISCUSSION: The symptoms of endometriosis and interstitial cystitis frequently overlap, and these 2 conditions may even coexist in the same patient. In cases of unresolved endometriosis and persistent pelvic pain, patients may have interstitial cystitis. A variety of tools are available to aid in identifying interstitial cystitis. CONCLUSION: Gynecologists should be alert to the possible presence of interstitial cystitis in patients who present with chronic pelvic pain typical of endometriosis.     

Uncommon causes of irritative lower urinary tract symptoms

Bladder symptoms accompanying a spectrum of disorders, ranging from urethral syndrome to interstitial cystitis, may be caused by potentially reversible factors. Some non-steroidal anti-inflammatory agents, particularly tiaprofenic acid, can cause frequency, urgency and suprapubic pain which is reversed upon discontinuing the medication. Anabolic steroids and GnRH agonists can on occasion cause bladder i irritability. Approximately half of women with bladder endometriosis have frequency and dysuria, usually without hematuria. Mycoplasma, ureaplasma and chlamydia are all associated with urethral syndrome. Cystitis may be caused by herpes simplex virus, herpes zoster, human T-lymphotrophic virus type 1, cytomegalovirus, toxoplasma and candida. Some work-related toxins may cause bladder effects without neoplasm. Foods high in tyrosine, tyramine and aspartate may exacerbate painful bladder syndrome. A search for potential non-bacterial sources of irritative lower urinary tract symptoms is warranted in evaluating women with such symptoms.EDITORIAL COMMENT: Irritative urinary tract symptoms — frequency, urgency, postvoid fullness and dysuria — are common complaints voiced by female patients of all ages. The evaluation of irritative lower urinary tract symptoms should include an extensive history, including onset, chronicity, severity, associated symptoms and inciting activities. A voiding and fluid intake diary should be obtained to assess daily patterns. Clinical tests to consider include urine culture and sensitivity, urethral and vaginal cultures, postvoid residual determination, cystourethroscopy, bladder washing or bladder biopsy. In most cases this evaluation will uncover the cause of the symptoms and guide appropriate treatment. However, in some instances the etiology of the symptoms remains unknown. Dr Nygaard presents a thorough review of uncommon causes of irritative lower urinary tract symptoms that we should all keep in mind.     

Chronic pelvic pain syndrome and the overactive bladder: The inflammatory link

Although the causes of chronic prostatitis/chronic pelvic pain syndrome, painful bladder syndrome/interstitial cystitis, and overactive bladder remain unclear, inflammation may explain some of the causative and propagating features. Cytokines may play a role by recruiting inflammatory cells and ultimately in inducing symptoms. This paper reviews the role of cytokines in the pathophysiology of chronic prostatitis/chronic pelvic pain syndrome, overactive bladder, and painful bladder syndrome/interstitial cystitis.     

Interstitial cystitis and painful bladder syndrome

PURPOSE: We quantified the burden of interstitial cystitis/painful bladder syndrome on the health care system in the United States. MATERIALS AND METHODS: The analytical methods used to generate these results were described previously. Interstitial cystitis was defined based on International Classification of Diseases, 9th revision code 595.1 (interstitial cystitis). For painful bladder syndrome we used the definition International Classification of Diseases, 9th revision code 788.41 (urinary frequency) with code 625.8 (other specified symptoms associated with female genital organs) or 625.9 (unspecified symptoms associated with female genital organs). RESULTS: Between 1992 and 2001 there was a 2-fold increase in the rate of hospital outpatient visits and a 3-fold increase in the rate of physician office visits related to interstitial cystitis. The annualized rate was 102 office visits per 100,000 population. Ambulatory surgery for interstitial cystitis decreased. A diagnosis of interstitial cystitis was associated with a 2-fold increase in direct medical costs. Between 1994 and 2000 annual national expenditures for interstitial cystitis were stable at $37 million but annual costs for painful bladder syndrome increased from $481 million to $750 million. CONCLUSIONS: Although interstitial cystitis accounts for a small percent of health care visits, its economic burden is substantial. Because of misdiagnosis, the true burden of interstitial cystitis/painful bladder syndrome on the health care system in the United States is probably underestimated in administrative data that rely only on physician coding to identify the disorder. The greatest part of the disease burden is likely not captured in this economic analysis.     

Intravesical drug delivery for dysfunctional bladder

The bladder is a hollow organ that can be treated locally by transurethral catheter for intravesical drug instillation or cystoscopy for intravesical drug injection. With advancing technology, local organ‐specific therapy and drug delivery is of expanding interest for treating dysfunctional bladder, including interstitial cystitis/bladder pain syndrome, overactive bladder and sterile hemorrhagic cystitis after chemotherapy or pelvic radiation. Intravesical therapy has shown varying degrees of efficacy and safety in treating interstitial cystitis/bladder pain syndrome, overactive bladder and hemorrhagic cystitis with new modalities being developed. Intravesical (regional) therapy has several advantages than oral (systemic) therapy, including high local concentration and less systemic toxicity. In recent years, intravesical delivery of biotechnological products including neurotoxins and immunosuppressive agents, and delivery platform including liposomes has shown promise for lower urinary tract symptoms. This review considers the current status of intravesical therapy in dysfunctional bladder including interstitial cystitis/bladder pain syndrome, overactive bladder and hemorrhagic cystitis with special attention to lipid based novel drug‐delivery.     

Clinical guidelines for interstitial cystitis/bladder pain syndrome

The clinical guidelines for interstitial cystitis and related symptomatic conditions were revised by updating our previous guidelines. The current guidelines define interstitial cystitis/bladder pain syndrome as a condition with chronic pelvic pain, pressure or discomfort perceived to be related to the urinary bladder accompanied by other urinary symptoms, such as persistent urge to void or urinary frequency in the absence of confusable diseases. The characteristic symptom complex is collectively referred as hypersensitive bladder symptoms. Interstitial cystitis/bladder pain syndrome is divided into Hunner-type interstitial cystitis and bladder pain syndrome; Hunner-type interstitial cystitis and bladder pain syndrome represent interstitial cystitis/bladder pain syndrome with Hunner lesions and interstitial cystitis/bladder pain syndrome without Hunner lesions, respectively. So-called non-Hunner-type interstitial cystitis featured by glomerulations or bladder bleeding after distension is included in bladder pain syndrome. The symptoms are virtually indistinguishable between Hunner-type interstitial cystitis and bladder pain syndrome; however, Hunner-type interstitial cystitis and bladder pain syndrome should be considered as a separate entity of disorder. Histopathology totally differs between Hunner-type interstitial cystitis and bladder pain syndrome; Hunner-type interstitial cystitis is associated with severe inflammation of the urinary bladder accompanied by lymphoplasmacytic infiltration and urothelial denudation, whereas bladder pain syndrome shows little pathological changes in the bladder. Pathophysiology would also differ between Hunner-type interstitial cystitis and bladder pain syndrome, involving interaction of multiple factors, such as inflammation, autoimmunity, infection, exogenous substances, urothelial dysfunction, neural hyperactivity and extrabladder disorders. The patients should be treated differently based on the diagnosis of Hunner-type interstitial cystitis or bladder pain syndrome, which requires cystoscopy to determine the presence or absence Hunner lesions. Clinical studies are to be designed to analyze outcomes separately for Hunner-type interstitial cystitis and bladder pain syndrome.     

Intravesical therapy for lower urinary tract symptoms

Intravesical (local) therapy for diseases emanating from the bladder is similar to the commonplace management of ocular diseases using eyedrops. The existing intravesical therapy involves administering dosage forms directly into the bladder (through a catheter). This mode of treatment is routine in the bladder cancer by instillation of bacillus Calmette–Guérin to provoke the body's own natural defenses against invasion by proliferating cancer cells in the bladder. Although convenient, the conventional routes of administration for treating diseases such as interstitial cystitis/painful bladder syndrome (IC/PBS) and overactive bladder (OAB) are less acceptable to patients owing to side effects, which may further exacerbate the disease symptoms. Intravesical therapy has demonstrated varying degrees of efficacy and safety in treating IC/PBS and OAB. In recent years, intravesical delivery of biotechnological products including neurotoxins using a liposome platform demonstrated immense promise for lower urinary tract symptoms. This review considers the current status of intravesical therapy in lower urinary tract diseases with special attention to novel drug-delivery systems.     

The Intravesical Potassium Sensitivity Test and Urodynamics: Implications in a Large Cohort of Patients with Lower Urinary Tract Symptoms

PURPOSE: Bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH) is the most common diagnosis in older men with lower urinary tract symptoms. However, these symptoms also can occur with interstitial cystitis. We determine whether the potassium sensitivity test is useful for distinguishing BPH from possible intersitial cystitis in patients with lower urinary tract symptoms. We also test the hypothesis that patients with these symptoms who have a positive test will have urodynamic findings consistent with the diagnosis of interstitial cystitis. MATERIALS AND METHODS: The potassium sensitivity test was performed in 526 (95%) males and 25 (5%) females with lower urinary tract symptoms undergoing urodynamic testing. Urodynamic parameters in the positive and negative potassium sensitivity test groups were compared. %Results: Of the patients 16% (89 of 551) had a positive potassium sensitivity test. Compared with patients who had a negative test, those who had a positive test were younger (61 versus 64 years, p = 0.03), had urgency at significantly lower volumes (108 versus 182 cc, p <0.0001), lower bladder capacity (343 versus 436 cc, p <0.0001) and lower post-void residual (49 versus 95 cc, respectively, p <0.001). Urodynamic parameters in the 24% (6 of 25) of women who had a positive potassium sensitivity test were similar to those in men who also had a positive test. CONCLUSIONS: Urodynamic findings in patients with lower urinary tract symptoms who have a positive potassium sensitivity test are significantly different from those in patients who have a negative test, and are similar to those findings characteristic of interstitial cystitis. Interstitial cystitis should be considered in patients with lower urinary tract symptoms who have a positive test. The potassium sensitivity and urodynamic tests may be a useful combination for screening men with lower urinary tract symptoms to identify those symptoms that may be due to interstitial cystitis versus BPH.     

Early Identification of Interstitial Cystitis May Avoid Unnecessary Hysterectomy

Background:

Interstitial cystitis is a clinical syndrome characterized by symptoms of pelvic pain, urinary urgency and frequency, and nocturia. It can be difficult to accurately identify interstitial cystitis because the symptoms overlap many other common gynecologic and urologic conditions. Patients with undiagnosed interstitial cystitis may undergo unnecessary procedures, including hysterectomy.

Methods:

A PubMed literature search for articles dating back to 1990 was conducted on the topics of interstitial cystitis and hysterectomy. Further references were identified by cross-referencing the bibliographies in articles of interest.

Results:

The literature review found that hysterectomy is performed more often in patients with undiagnosed interstitial cystitis than in patients with a confirmed diagnosis. Interstitial cystitis often coexists with conditions like endometriosis, for which hysterectomy is indicated. Many patients subsequently diagnosed with interstitial cystitis continue to experience persistent pelvic pain despite having had a hysterectomy for chronic pelvic pain. Careful history and physical examination can identify the majority of interstitial cystitis cases.

Conclusion:

Interstitial cystitis should be considered prior to hysterectomy in women who present with pelvic pain or who experience pelvic pain after a hysterectomy. If interstitial cystitis is diagnosed, appropriate therapy may eliminate the need for hysterectomy.     

Phenotyping of interstitial cystitis/bladder pain syndrome

Interstitial cystitis/bladder pain syndrome is a chronic, potentially debilitating condition characterized by pain perceived to be related to the bladder in conjunction with lower urinary tract symptoms, and includes a wide variety of clinical phenotypes with diverse etiologies. Currently the only clinically relevant proven phenotype of interstitial cystitis/bladder pain syndrome is the Hunner lesion. Whether the presence of Hunner lesions is a hallmark of a distinct disease cohort or a potentially transient feature of non‐Hunner lesion phenotype has been debated but remains controversial. There are few documented examples of a patient converting between the two forms. Growing clinical and basic evidence supports eliminating the Hunner lesion phenotype from the bladder pain syndrome umbrella and considering it a distinct disease. The Hunner lesion phenotype is characterized by distinct bladder histology, including subepithelial chronic inflammatory changes and epithelial denudation, and specific clinical characteristics (older onset age, severe bladder‐centric symptoms, reduced bladder capacity, and favorable response to the lesion‐targeted therapies). To define the Hunner lesion phenotype, it is necessary to develop an atlas of standardized images of cystoscopic (and, if possible, pathological) appearances of Hunner lesions. A true potential and clinically relevant phenotype of interstitial cystitis/bladder pain syndrome may be patients with non‐bladder‐centric symptoms, characterized by the affect dysregulation and somatic symptoms, and a greater bladder capacity in absence of Hunner lesions. In the present workshop, we concluded that the Hunner lesion is a valid phenotype and can reasonably be considered a disease in its own right. Assessment of bladder capacity and the extent of symptoms (bladder beyond or bladder centric) may help phenotyping of interstitial cystitis/bladder pain syndrome. Proper phenotyping is essential for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome, and for facilitating research.     

Interstitial cystitis: how should we diagnose it and treat it in 2004?

PURPOSE OF REVIEW: During the last 2 years, two international and two European meetings have taken place and a European Society formed dealing only with interstitial cystitis. A separate committee for interstitial cystitis was formed during the last WHO International Consensus Meeting on urinary incontinence. As a consequence, new concepts and recommendations are evolving, for example the nomenclature is changing from interstitial cystitis to painful bladder syndrome/interstitial cystitis. RECENT FINDINGS: At an international meeting in Kyoto, the scientific basis for diagnosis and treatment of painful bladder syndrome/interstitial cystitis was reviewed, confirming the poor evidence for many diagnostic procedures and treatments. There are two main reasons for this: an internationally accepted definition is lacking and the disease is rare, making clinical trials difficult. A meeting in Copenhagen resulted in a standardization of the procedures for evaluation and the creation of a European Society for the Study of Interstitial Cystitis. Increased concentration of nitric oxide in the urine of patients with Hunner's ulcer may help to separate ulcer from non-ulcer patients. A prospective, randomized, placebo-controlled multicenter study failed to show a statistically significant effect of the antihistamine hydroxine or pentosan polysulfate sodium compared with placebo. The study confirmed the difficulties in recruiting patients for large-scale trials, which could be one of the reasons for the negative result. The effect of the traditional treatment with amitriptyline was confirmed in a prospective, placebo-controlled study. SUMMARY: Standardized evaluation of patients with painful bladder syndrome/interstitial cystitis will benefit both patients and science. An internationally accepted definition of the condition appears to be in sight, which will make epidemiological and research studies easier.     

Pathophysiology of interstitial cystitis

Interstitial cystitis/bladder pain syndrome is a chronic pain syndrome whose causes remains elusive with no generally accepted treatment. A hallmark of functional pain syndromes such as interstitial cystitis/bladder pain syndrome is pain in the absence of demonstrable pathology of the viscera or associated nerves. Patients with chronic pain experience a greater impairment in quality of life than healthy controls. In addition, interstitial cystitis/bladder pain syndrome symptoms can frequently overlap with other conditions including irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, anxiety disorders, and a number of other syndromes not directly related to the urinary bladder. Because of the complex pathophysiology, a number of animal models have been studied over the years to better understand mechanisms underlying patient symptoms. These models can include: bladder centric, complex mechanisms and psychological and physical stress models. Such animal models can aid in the investigation of aspects of interstitial cystitis/bladder pain syndrome that cannot be pursued in humans as well as to develop and test potential therapies. In addition, the search for urinary factors that may be a cause of interstitial cystitis/bladder pain syndrome has resulted in the discovery of a number of potential targets that could serve as predictive biomarkers which can aid in early diagnosis and treatment of this chronic disorder.     

HOW DO PATIENTS WITH INTERSTITIAL CYSTITIS PRESENT?

PURPOSE: We determined how interstitial cystitis progresses from initial symptoms to diagnosis. MATERIALS AND METHODS: We retrospectively analyzed the records of 45 patients to determine the dates of symptom onset and diagnosis, and sequence of urgency/frequency, nocturia and pain. We also documented alternate and previous diagnoses, and previous surgical treatments. RESULTS: Of the patients 89% presented with only 1 symptom. Median time from the initial symptom to all symptoms was 2 years (mean 5.5). The most common previous diagnoses were urinary infection in 19 cases, a gynecologic diagnosis in 14 and urethral diagnoses in 6. A previous urinary infection was documented in only 1 of 19 patients, while 11 had undergone hysterectomy and 5 diagnosed with endometriosis had no pathological documentation available. CONCLUSIONS: Early interstitial cystitis presents variably and usually with only a single symptom of urgency/frequency, nocturia or pain. Clinicians may fail to appreciate the symptoms of early interstitial cystitis, which leads to delayed diagnosis until the patient is more symptomatic. With time multiple symptoms manifest. Bacterial cystitis, prostatitis, endometriosis and chronic pelvic pain are common initial misdiagnoses. Interstitial cystitis should be considered when laboratory documentation of alternate diagnoses is lacking or when patients fail to respond to therapy for alternate diagnoses.     

Painful bladder syndrome/interstitial cystitis and vulvodynia: a clinical correlation

Vulvodynia affects 25% of women with painful bladder syndrome/interstitial cystitis (PBS/IC). The objective of our study was to clinically evaluate the association of PBS/IC and vulvodynia and possible contributing factors. To our knowledge, this has not been reported. Seventy women with PBS/IC were evaluated from December 2005 to December 2006 with a comprehensive history and exam. Two groups were formed—those with vulvodynia and those without vulvodynia for comparison. Of the women, 51.4% had vulvodynia and 48.6% did not have vulvodynia using our operative definition. Average levator pain levels were significantly greater in those with vulvodynia. There was no significant difference in the total number of lifetime pelvic surgeries, history of sexually transmitted infections (STIs), vaginitis, or abuse history between groups. The correlation of vulvodynia and PBS/IC may have been underestimated. Research needs to explore the link between precipitating factors, symptoms, and effective treatment options for PBS/IC and vulvodynia.     

Voiding Dysfunction in the Female Patient: Is the “Syndrome” Paradigm Valid?

Voiding dysfunction in the female patient significantly affects the patient’s quality of life. The condition is poorly understood, has varied etiology and clinical presentation, and lacks standard definitions with no consensus on diagnostic criteria. It consists of a constellation of symptoms involving both phases of the micturition cycle. Appropriate diagnosis and treatment of female lower urinary tract symptoms (LUTS) is of paramount importance. However, the differentiation of female LUTS into various syndromes is currently controversial. This article comprehensively reviews the commonly encountered female non-neurogenic LUTS (overactive bladder, interstitial cystitis, and painful bladder syndrome); discusses the contemporary management of these syndromes; and emphasizes a syndromic approach to the condition.     

Bladder pain syndrome/interstitial cystitis: a sense of urgency

A classic triad of symptoms (bladder pain, urinary frequency, and urgency) has served to define bladder pain syndrome/painful bladder syndrome/interstitial cystitis (BPS/PBS/IC) syndrome. BPS/PBS/IC is a distinct condition and it is likely that the urgency experienced by these patients differs from that experienced by those with overactive bladder syndrome. It is unclear how best to define urgency in the BPS/PBS/IC setting. Differences in the other primary symptoms associated with these conditions probably influence how urgency is perceived. Advances in research into the pathophysiology of urgency and underlying disease processes will help to optimize both the diagnosis and treatment of BPS/PBS/IC.     

The Overlap of Interstitial Cystitis/Painful Bladder Syndrome and Overactive Bladder

Objective:

We evaluated the prevalence of positive potassium sensitivity and cystoscopy with hydrodistention findings in patients with overactive bladder.

Method:

This was a prospective cohort study of 98 patients who presented with overactive bladder symptoms. The diagnosis of overactive bladder is established by the presence of irritable voiding symptoms. All patients completed a PUF questionnaire and underwent potassium sensitivity testing. Eighty patients underwent urodynamic testing, and 42 patients underwent cystoscopic hydrodistention while under general anesthesia.

Results:

The Potassium Sensitivity Test was positive in 59 (60.2%) of the 98 patients, 37 (56%) of wet overactive bladder patients, and 22 (68.8%) of dry overactive bladder patients. Their mean PUF score was 7. Thirty-three (78.5%) of the patients who underwent cystoscopic hydrodistention had glomerulations consistent with NIH criteria for interstitial cystitis, and 26 of these patients tested positive for potassium sensitivity. Fifty-one (63.8%) of the patients who underwent urodynamics tested positive for potassium sensitivity.

Conclusion:

Many patients with symptoms of overactive bladder with little or no pain have cystoscopic evidence of interstitial cystitis and a positive Potassium Sensitivity Test. Therapies directed toward the uroepithelial dysfunction and neural upregulation associated with interstitial cystitis/painful bladder syndrome may be an important adjunct for patients who have failed or have had a partial response to anticholinergic therapy and behavior modification.     

Urgency is the core symptom of female overactive bladder syndrome, as demonstrated by a statistical analysis

PURPOSE: We determined overactive bladder symptoms in combination with other lower urinary tract symptoms and illustrated their relationships using a statistical analysis. Furthermore, we also describe the potential contributory factors and adaptation strategies in patients that are associated with overactive bladder subtypes. MATERIALS AND METHODS: A total of 1,930 women with a mean age +/- SD of 46 +/- 15 years (range 15 to 91) with troubling lower urinary tract symptoms were successfully interviewed with a validated questionnaire at the urology and urogynecology clinics at 14 medical centers in Taiwan. The questionnaire was constructed to evaluate 6 lower urinary tract symptoms and 7 adaptation strategies. A log linear statistical model and multiple logistic regression analysis were used to assess the associations among lower urinary tract symptoms and the potential overactive bladder contributory factors, respectively. RESULTS: No single or isolated symptom presented in patients with overactive bladder. Most patients reported a combination with other lower urinary tract symptoms. These female patients can be categorized into 3 groups, including 1 is associated with dry symptoms (urgency, frequency and nocturia), 1 associated with wet symptoms (urgency, urge incontinence and mixed stress incontinence) and a small group that may have overactive bladder symptoms combined with voiding difficulty symptoms. in contrast to patients with dry overactive bladder (urgency associated with frequency and/or nocturia without urge incontinence), after multiple logistic regression analysis patients with wet overactive bladder (urgency with urge incontinence) had a greater average age and higher body mass index, and made more adaptation efforts (p <0.05). CONCLUSIONS: We used statistical analysis to determine and suggest that urgency is the core symptom of female overactive bladder syndrome and there are 3 distinctive overactive bladder subtypes, which differ in their symptom combinations. Different symptom combinations and patient characteristics affect female adaptation to overactive bladder syndrome.