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.     

Surgical management of intractable interstitial cystitis

Interstitial cystitis represents a diagnostic and therapeutic challenge. Most patients can be managed conservatively, but a small number of patients do not respond to conservative therapy and for them surgical treatment is indicated. This article reviews the historical and currently used surgical modalities. Enterocystoplasty is the surgical treatment of choice for intractable interstitial cystitis. The results of enterocystoplasty are satisfactory in approximately 80% of patients. However, no histological findings, such as mast cell density or degree of inflammation, can be used as a preoperative predictor of treatment results. The best results of cystoplasty seem to be achieved in patients who have a small bladder capacity, determined preoperatively under anesthesia. Approximately 10%–20% of patients may not be able to void spontaneously after surgery and require self-catheterization. Because of the unpredictable results, cystoplasty must be recommended with caution for certain patients. There is no evidence to indicate that a supratrigonal cystectomy and substitution cystoplasty offer a therapeutic advantage over augmentation cystoplasty alone. The choice of bowel segment does not affect the final outcome provided that it is tubularized and made spherical in configuration.     

Hyperbaric oxygen therapy for interstitial cystitis resistant to conventional treatments

We treated two cases of interstitial cystitis (IC) that were resistant to some conventional therapies with hyperbaric oxygen (HBO). Both patients underwent 20 sessions of 100% oxygen inhalation (2.0 atmosphere absolute for 60 min/day x 5 days/week for 4 weeks) in a hyperbaric chamber. The period of follow up was 12 months for case 1 and 9 months for case 2. After a course of HBO, the bladder mucosal ulcer (Hunner's ulcer) disappeared, and changes from baseline in pain and urinary frequency was constitutively inhibited. There were no adverse events during the 20 treatment sessions. One woman (case 1) had mild Eustachian tube dysfunction, resulting in a transient hearing impairment. HBO seems to be an option for treatment of IC resistant to conventional therapies.     

Psychological profile of Taiwanese interstitial cystitis patients

Objectives:   The correlation between anxiety and interstitial cystitis has, as best we know, not yet been reported on. The present study investigated the psychological profile, including anxiety and depression, of patients suffering from interstitial cystitis (IC).
Methods:   A total of 47 IC patients, all of whom met National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (NIDDK) criteria, plus a group of 31 age-matched, asymptomatic women received a structured interview on depression (Hamilton Rating Scale for Depression) and also on anxiety symptoms (Hamilton Rating Scale for Anxiety). IC patients also completed questionnaires relating to IC symptom severity, including urgency and frequency (visual analog scale) and O'Leary Sant index.
Results:   A total of 85% of our IC patients featured significant affective symptoms. The average depression scores were 16.6. Fifteen patients (31.9%) featured mild depressive symptoms, five (10.6%) had mild to moderate and 20 (42.6%) had moderate to severe depression symptoms. The mean anxiety score was 21.0, with 21 (44.7%), nine (19.1%) and 17 (36.2%) patients revealing mild, mild to moderate, and moderate to severe anxiety symptoms, respectively. Further, IC patients reported a significantly greater extent of depression and anxiety than was the case for controls. Pain scale and O'Leary Sant index were significantly correlated to anxiety and depression score.
Conclusions:   Most of our IC patients feature significant depression and anxiety. The extent of affective symptoms would appear to correlate well with IC symptom severity.     

Abnormal pedal thermoregulation in interstitial cystitis

Isolated cold stress tests were used to evaluate the thermoregulatory capacity in the feet of 19 patients with interstitial cystitis (IC) and of 11 healthy volunteer control subjects. Mean pedal skin temperature fell more rapidly in the IC group as compared with controls; significant differences were found at 10-min (P = 0.002) and 20-min (P = 0.0008) cooling. Mean skin temperature remained lower in the IC group throughout the study. Sixteen feet (42%) in the IC group and five (22%) of the control feet failed to return to within 2°C of baseline temperature during the 20-min recovery period. These findings may reflect abnormal vasomotor control in the IC group and, if so, may be indicative of increased spinal sympathetic activity in interstitial cystitis.     

Abnormal sensitivity to intravesical potassium in interstitial cystitis and radiation cystitis

The urgency-frequency syndrome (UFS) (non-bacterial cystitis, interstitial cystitis) may well represent a heterogenous group with several etiologies. This study was based on the hypothesis that one subset of UFS patients has a leaky (to solutes) epithelium and cations such as potassium could thereby diffuse subepithelially and provoke symptoms. It was also hypothesized that normal impermeable transitional epithelium would not allow cations to diffuse across the cells during the K + provocation test and no symptoms would be experienced. If the epithelium was permeable (“leaky”), diffusion would occur and provoke symptoms. Water or 0.4 M KCl was placed intravesically into normal volunteers and interstitial cystitis (IC) patients. Water did not provoke symptoms in either group but KCl provoked 45% of normals and 70% of IC patients. Differences were significant (P < 0.0001). This test provides a valuable diagnostic tool for UFS and a valuable research tool to separate epithelial permeability problems from other subsets of patients. A third group, consisting of 11 IC patients in remission on heparinoid therapy, was also tested and only 18% were provoked by KCl. Four patients with radiation cystitis were also examined and all four (100%) were provoked by the potassium. © 1994 Wiley-Liss, Inc.     

Toward a precise definition of interstitial cystitis: further evidence of differences in classic and nonulcer disease

PURPOSE: Interstitial cystitis is a bothersome condition in urological practice. There is continuous discussion on the extent and demarcation of this syndrome. Accumulated evidence indicates that interstitial cystitis is a heterogeneous syndrome. Today it is often divided into classic and nonulcer disease. Compared with classic interstitial cystitis the nonulcer type appears different in terms of demographic, endoscopic and histological findings as well as in the response to various types of treatment. However, in clinical series subdivision is not always performed, which makes it difficult to draw conclusions. We determined whether there are additional dissimilarities in clinical presentation in the 2 subtypes of interstitial cystitis. MATERIALS AND METHODS: We evaluated 130 patients with classic and 101 with nonulcer interstitial cystitis diagnosed according to National Institute for Diabetes and Digestive and Kidney Diseases criteria by surveying the clinical records, including voiding diaries. RESULTS: Patients with nonulcer disease were younger at diagnosis (p <0.0001) and at symptom onset. Furthermore, there was a marked and significant difference in bladder capacity while patients were under general anesthesia (p <0.0001). CONCLUSIONS: The current findings together with previous findings clearly demonstrate that the 2 subtypes of interstitial cystitis represent separate entities. We suggest refining the National Institutes of Health-National Institute for Diabetes and Digestive and Kidney Diseases criteria, so that subtyping scientific materials is considered mandatory, hence, ensuring that the 2 subtypes are evaluated separately in clinical studies.     

Is interstitial cystitis an allergic disorder?: A case of interstitial cystitis treated successfully with anti-IgE

Interstitial cystitis (IC) is a chronic disorder diagnosed by symptomatology of pelvic pain and urinary frequency, which are extremely variable and unpredictable fluctuating among patients. IC has recently been found combined with some allergic disorders and histopathologic abnormalities resembling that of allergic disorders, including mast cell activation, histamine release and eosinophil infiltration. Therefore, it could be cautiously postulated that IC is one of the allergic disorders of the urogenital system. A 28-year-old Caucasian female patient, who was diagnosed with asthma and allergic rhinitis, suffered from bladder symptoms of frequency, urgency and pelvic pain for the past 3 years. The symptoms disturbed her every day and were intractable for treatment. Urologists concluded that she had interstitial cystitis. Specific immunotherapy (SIT) was recommended for her allergic symptoms. While taking specific immunotherapy, she had anaphylaxis. She still had the reaction even with the 1000-fold diluted shot of SIT. Omalizumab was used for her allergic symptoms and possible prevention of anaphylactic reaction to SIT. Interestingly, she reported that her urogenital symptoms had subsided since omalizumab had been started. According to the published literature, we postulate that interstitial cystitis might be one of the IgE mediated, mast cell driven allergic disorders of the urogenital system. Therefore, in this case, the patient's bladder symptoms are successfully controlled primarily by anti-IgE therapy and the improvement could be maintained by SIT. We report, for the first time, a case of interstitial cystitis with allergic rhinitis and asthma, successfully treated by anti-IgE therapy and specific immunotherapy.     

Subtypes of bladder mast cells in interstitial cystitis

BACKGROUND: Because the types of mast cells present in the bladder of patients with interstitial cystitis (IC) have not been elucidated, we have used immunohistochemical techniques to determine which of the mast cell types is present in biopsy specimens. METHODS: For all patients diagnosed with IC (n = 10; female) their symptoms satisfied the criteria proposed by the National Institutes of Health criteria of IC and six patients suffering from bladder tumors were selected as control patients. Adjacent sections of paraffin-embedded tissues that had been fixed in Carnoy's solution were reacted with either antitryptase or antichymase antibodies. RESULTS: In detrusor and in mucosa, the number of tryptase-positive and chymase-negative mast cells (MC(T)) was 146+/-25 and 81+/-31 cells/mm2, respectively, and the number of tryptase-positive and chymase-positive mast cells (MC(TC)) was 124+/-50 and 54+/-20 cells/mm2, respectively. These numbers were significantly greater than those of the control group. A significant negative correlation (P<0.005; R = 0.943) was observed between the number of MC(TC) and the bladder capacity. The number of mast cells obtained by toluidine blue staining in detrusor and in mucosa was 95+/-68 and 71+/-39 cells/mm2, respectively, suggesting that staining with toluidine blue underestimated the number of mast cells. CONCLUSIONS: Mast cells were significantly increased in number in both the mucosa and detrusor of bladder specimens from IC patients compared with those from control. The MC(TC) may be the type of mast cell dominantly present in the bladder of IC patients. The MC(TC) in detrusor increased with the progression of contracted bladder.     

Clinical guidelines for interstitial cystitis and hypersensitive bladder syndrome

A clinical guideline and algorism for interstitial cystitis and hypersensitive bladder syndrome has been developed by a group of East Asian urologists as a revised form of the Japanese guideline for interstitial cystitis. The guideline defines interstitial cystitis (IC) as a disease of the urinary bladder diagnosed by 3 requirements; 1) a characteristic complex of lower urinary tract symptoms, 2) bladder pathology such as Hunner's ulcer and bladder bleeding after overdistension, and 3) exclusions of confusable diseases. The characteristic symptom complex is termed as hypersensitive bladder syndrome (HBS), which is defined as bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain. For the definite diagnosis of IC, cytoscopy or hydrodistension is crutial; HBS is the diagnosis when IC is suspected but not confirmed by the 3 requirements. Numerous therapeutic options are available; however, most of them lack in high level of evidence, leaving a few as recommended therapies. Etiology of IC are multifactorial; the interaction among nervous, immune and endocrine factors forms a vicious cycle, provocating and maintaining inflammatory reactions in the bladder. The inclusion and efficacy criteria for clinical trials should be standardized to enhance the clinical research for this disabling disease, which has proved to be more prevalent than previously believed.     

多药联合治疗间质性膀胱炎的临床分析

目的:探讨多种药物联合治疗间质性膀胱炎(IC)的有效性和安全性。方法:24例女性IC患者,平均年龄(43.4±8.9)岁,随机分为A、B两组,每组12例。A组口服阿米替林、托特罗定;B组除口服A组药物外加用碱化利多卡因联合肝素膀胱灌注治疗,将2%利多卡因15ml+肝素50 000U+5%碳酸氢钠10ml+0.9%氯化钠10ml混合液行膀胱灌注,保留30min,每周两次。观察并对比A、B两组治疗前及治疗后3个月和6个月每日排尿次数、最大排尿量、疼痛评分,O’Leary-Sant IC评分和生活质量评分(QOL)情况。并记录不良反应发生情况。结果:①治疗3个月和6个月后,A、B两组各项指标明显改善,分别与治疗前相比差异均有统计学意义(P<0.05);而且,治疗后相同时间段A、B两组各项指标之间差异也均有统计学意义(P<0.05)。治疗后不同时间段,A组各项指标之间差异无统计学意义(P>0.05),而B组各项指标之间差异均有统计学意义(P<0.05)。②A、B两组患者全部接受完治疗,A组中共有3例出现倦怠、2例出现口干,均可耐受;B组中2例出现倦怠,2例灌注后出现轻度肉眼血尿,均自行缓解。结论:阿米替林、托特罗定同时使用是治疗IC合适的口服药物方案,而服药同时早期就进行利多卡因加肝素膀胱灌注的联合治疗方案,不仅能够显著提高IC治疗的短期效果,也可以增加远期疗效,而且耐受性和安全性较好,是值得临床推广的方案。     

Intravesical nitric oxide production discriminates between classic and nonulcer interstitial cystitis

PURPOSE: Interstitial cystitis (IC) is one of the most bothersome conditions in urological practice. There are 2 subtypes, classic and nonulcer IC, with similar symptoms but different outcomes with respect to clinical course and response to treatment. Histologically there are fundamental differences between the 2 subtypes, classic IC presenting a severe abnormality of the urothelium and characteristic inflammatory cell infiltrates while inflammation is scant in nonulcer IC. Regulation of urinary nitric oxide synthase activity has been proposed to be of importance for immunological responses in IC. We present evidence of a profound difference between the 2 subtypes concerning nitric oxide production, mirroring the differences in inflammatory response in IC.MATERIALS AND METHODS: A total of 17 patients with both subtypes and active disease as well as patients with disease in remission were included in the study, all diagnosed according to National Institute for Diabetes and Digestive and Kidney Diseases criteria. Luminal nitric oxide was measured in the bladder of patients using a chemiluminescence nitric oxide analyzer. RESULTS: All patients with classic IC had high levels of NO. None of the other patients had any significant increase in NO levels in the bladder. The NO level in patients with classic IC was not related to symptoms but rather to the assignment to this specific subgroup of IC. The highest levels of NO were found in patients in the initial phase of classic IC. CONCLUSIONS: The difference in NO evaporation between classic and nonulcer IC allows for subtyping of cases meeting National Institute for Diabetes and Digestive and Kidney Diseases criteria without performing cystoscopy. The findings in the present series together with previous findings clearly demonstrate that the 2 subtypes of IC represent separate entities. This separation further emphasizes the need to subtype all cases included in all scientific matters, ensuring that the 2 subtypes are evaluated separately in clinical studies.     

Role of liposome in treatment of overactive bladder and interstitial cystitis

Intravesical (local) therapy of agents has been effective in delaying or preventing recurrence of superficial bladder cancer. This route of drug administration has also shown tremendous promise in the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS) and overactive bladder without systemic side effects. Liposomes are lipid vesicles composed of phospholipid bilayers surrounding an aqueous core. They can incorporate drug molecules, both hydrophilic and hydrophobic, and show greater uptake into cells via endocytosis. Intravesical liposomes have therapeutic effects on IC/PBS patients, mainly because of their ability to form a protective lipid film on the urothelial surface. Recent studies have shown the sustained efficacy and safety of intravesical instillation of botulinum toxin formulated with liposomes (lipo-BoNT) for the treatment of refractory overactive bladder This review considers the current status of intravesical liposomes or liposomal mediated drug delivery for the treatment of IC/PBS and overactive bladder.