Hyaluronan treatment of interstitial cystitis/painful bladder syndrome

The aim of this study is to evaluate the efficacy of intravesical hyaluronan therapy in interstitial cystitis/painful bladder syndrome (IC/PBS). One hundred twenty-six patients with IC/PBS and an average disease duration of 6.1 years were treated with weekly instillations of a 50-cm³ phosphate-buffered saline solution containing 40 mg sodium hyaluronate. To be eligible for hyaluronan treatment, a positive modified potassium test was requested as a sign of a urine–tissue barrier disorder. Data were obtained by a visual analogue scale (VAS) questionnaire rating from 0 to 10 that asked for global bladder symptoms before and after therapy. Additional questions evaluated the therapeutic impact on quality of life. A positive and durable impact of hyaluronan therapy on IC/PBS symptoms was observed—103 (85%) of the patients reported symptom improvement (≥2 VAS units). The mean initial VAS score of 8.5 decreased to 3.5 after therapy (p < 0.0001). Out of 121 patients, 67 (55%) remained with no or minimal bladder symptoms after therapy (VAS 0–2). The majority (101, 84%) reported significant improvement of their quality of life. Intravesical therapy had to be initiated again with good success in 43 patients (34.5%) as symptoms recurred after discontinuation of treatment, while the rest stayed free of symptoms for up to 5 years. In general, hyaluronan therapy was well tolerated and, with the exception of mild irritative symptoms, no adverse reactions were reported for a total of 1,521 instillations. Timely hyaluronan instillation therapy may lead to complete symptom remission or even cure in part of the IC/PBS patients, while some responders need continuous intravesical therapy. The present results suggest that selection of patients for hyaluronan therapy by potassium testing improves the outcome of intravesical therapy with a response rate of >80%.     

Is there a relation between urinary interleukin-6 levels and symptoms before and after intra-vesical glycosaminoglycan substitution therapy in patients with bladder pain syndrome/interstitial cystitis?

Urinary interleukin-6 (IL-6) has been proposed as a sensitive and specific inflammatory marker in bladder pain syndrome/interstitial cystitis (BPS/IC). We therefore investigated the presence of urinary IL-6 in patients with BPS/IC to find a possible correlation with the symptoms before and after glycosaminoglycan substitution therapy. Urinary IL-6 levels of 25 BPS/IC patients were assessed semi-quantitavely (Milenia®Quickline) before and after intra-vesical glycosaminoglycan substitution therapy. Patients received therapy twice weekly with 300 mg pentosanpolysulphate for 5 weeks. Responders were treated for another 5 weeks, whilst non-responders received 40 mg hyaluronic acid weekly for another 10 weeks instead. Treatment response was assessed by the visual analogue scale (VAS) for quality of life and O’Leary–Saint Symptom and Problem Index (OSPI) before, during the 5th week of the treatment and 1 week after the treatment. Before treatment, measurable IL-6 was found in urine samples from 9 out of 25 patients. After treatment, urinary IL-6 was detected in two patients only. The average VAS and OSPI scores before the treatment were 7.9 (4–10) and 25.4 (12–37), respectively. After the treatment, the average VAS and OSPI scores dropped to 5.5 (0–10) and 14.7 (1–29), respectively. No statistically significant difference was found between patients with and without urinary IL-6 and the VAS and OSPI scores before and after the treatment. The urinary IL-6 level in BPS/IC patients is neither suited as a diagnostic marker nor as a predictor of responses to therapies. For the future, it would be important to clarify whether there are subsets of patients with diseases of different aetiologies.     

Histological changes in interstitial cystitis

Various aspects of the histological appearance of the bladder wall in interstitial cystitis have been emphasized over the 75 years since Hunner described the condition. The major focus of interest in this disease during the last decade has been the study of the relative significance of detrusor mastocytosis. Although this was for some years considered pivotal in establishing a diagnosis of interstitial cystitis, most recent studies have not shown mastocytosis to be a consistent feature of the disease. The histological picture of this condition is now considered to be that of a chronic inflammatory infiltrate of the lamina propria, possibly with fibrosis of the detrusor or lamina propria. The authors attempted to determine if there is a correlation between the severity of inflammation and fibrosis, and detrusor mastocytosis, on initial biopsy and the response of symptoms to conservative treatment. Of 39 patients, 10 required major surgical intervention. Although not reaching statistical significance, most cases with mild disease responded to conservative management. However, over 50% of cases showing severe histological disease also responded well to this type of treatment. Histological assessment of the interstitial cystitis bladder is more useful in ruling out other diseases than in allowing the demonstration of specifical diagnostic features of this condition. A severely abnormal microscopic picture does not necessarily indicate a poor prognosis.     

肝素膀胱灌注治疗间质性膀胱炎

目的　观察肝素膀胱灌注治疗间质性膀胱炎的疗效。　方法　 17例间质性膀胱炎患者 ,均为女性。平均年龄 35岁。平均病程 2 7个月。临床表现主要为尿频及膀胱区疼痛。膀胱镜检见黏膜下点状出血 15例 ,Hunner溃疡 2例。按O’Leary Sant间质性膀胱炎症状评分 (ICSI) 8～ 18分 ,平均 (13.4± 3.5 )分 ;问题评分 (ICPI) 3～ 12分 ,平均 (8.2± 3.4 )分。所有患者均使用肝素钠 10 5U膀胱灌注 ,每周 3次 ,疗程 4周。观察治疗后患者症状改善情况。　结果　 17例患者随访 3～ 12个月 ,平均 6个月 ,症状缓解 14例 ,其中症状显著缓解或消失 9例 ,评分下降 7分 ;症状部分缓解 5例 ,评分下降 >3分 ;无效 3例。 2例于治疗 7个月及 9个月症状复发。有效率 82 %。治疗后 1、2个月ICSI分别降至 (6 .1± 3.4 )、(6 .3± 3.5 )分 ,ICPI分别降至 (3.5± 2 .9)、(3.6± 2 .7)分 ,治疗前后比较差异有显著性意义 (P <0 .0 1)。治疗期间发生一过性尿道灼痛者 2例 ,轻微肉眼血尿 1例。　结论　肝素膀胱灌注治疗可有效缓解间质性膀胱炎患者症状 ,提高生活质量。     

The role of the glycosaminoglycan layer in bladder defense mechanisms and interstitial cystitis

The bladder surface glycosaminoglycan layer is an important defense mechanism for the transitional epithelium. It allows adaptation to the constant exposure to urine, and controls the permeability of urinary substances to the transitional cell. This layer seems to be impaired in some patients with interstitial cystitis.     

阿米替林治疗间质性膀胱炎的临床研究

目的 探讨阿米替林治疗间质性膀胱炎的有效性和安全性. 方法 采用前瞻性研究.间质性膀胱炎患者54例,病程19～72个月,平均(40.7±11.6)个月.口服阿米替林治疗,起始剂量25 mg/次,每晚1次.1周后,若症状不缓解,可加量至50 mg/次;再观察1周,若症状仍不缓解,则可加量至75 mg/次;维持能够缓解症状的最小剂量,总疗程3个月.观察用药前及用药3个月后患者的临床症状(每日排尿次数、最大排尿容量、尿痛程度评分)和O'Leary-Sant间质性膀胱炎问卷表评分及生活质量评分情况.并记录不良反应发生情况. 结果 ①用药3个月后每日排尿次数明显减少,治疗前后分别为(28.5±8.4)和(15.6±3.3)次;最大排尿容量明显增加,治疗前后分别为(108.7±62.2)和(171.0±53.9)ml;尿痛程度评分明显下降,治疗前后分别为6.4±1.5和2.2±1.5,上述指标用药前后相比,差异均有统计学意义(P<0.01).②患者用药3个月后问卷评分和生活质量评分均明显减少,治疗前后分别为26.9±4.0和13.7±5.7及5.5±0.5和2.5±0.6;用药前后比较,差异有统计学意义(P<0.01).③45例在服药第1个月内有不同程度的困倦,43例1个月后自行缓解,2例由于困倦严重且不能缓解而停药.10例服药3个月后体质量增加(5.8±1.8)kg.11例有轻度便秘症状,可以耐受.9例有口干症状,可以耐受.3例出现重度排尿困难,停药后改为其他方法治疗. 结论 阿米替林口服治疗能有效缓解间质性膀胱炎患者的临床症状,改善生活质量,且耐受性及安全性好.     

膀胱水扩张联合灌注树胶脂毒素治疗间质性膀胱炎的疗效分析

目的 评价使用腰麻下膀胱水扩张联合灌注树胶脂毒素(RTX)治疗间质性膀胱炎(IC)的疗效.方法 回顾性分析16例间质性膀胱炎患者,均使用腰麻下行水扩张加RTX膀胱灌注.评价治疗前、后1个月以及6个月的排尿次数,排尿量以及临床症状比较.结果 所有患者治疗前与治疗后1个月以及6个月的排尿频率、最大膀胱容量以及临床症状评分相...     

血小板衍化内皮细胞生长因子/胸腺嘧啶磷酸酶和血管内皮生长因子在间质性膀胱炎诊断中的应用

目的 检测血小板衍化内皮细胞生长因子/胸腺嘧啶磷酸酶(PDECGF/TP)和血管内皮生长因子(VEGF)的表达,探讨血管生长因子在间质性膀胱炎(IC)患者膀胱中的表达活性与膀胱镜下的表现及临床症状的关系.方法 选择符合NIH/NIDDK诊断标准的IC患者12例为实验组和12例Ⅲ型前列腺炎患者为对照组.实验组行麻醉下水扩张,膀胱组织活检,常规苏木素-伊红(HE)染色观察肥大细胞数量.应用免疫组织化学检测PDECGF/TP和VEGF表达,进行免疫组织化学阳性细胞计数及免疫组织化学评分(IHS).结果 实验组12名患者在麻醉下水扩张时发现膀胱黏膜点片状出血.常规HE染色病理切片观察可见IC组膀胱组织标本中肥大细胞数目明显高于对照组(P＜0.05),且IC患者的肥大细胞多存在于膀胱组织的黏膜下层,而对照组膀胱组织仅偶见肥大细胞.实验组患者膀胱黏膜PDECGF/TP和VEGF阳性细胞百分比计数、阳性细胞染色强度及HIS评分明显高于对照组(P＜0.05).结论 IC患者血管生长因子PDECGF/TP和VEGF呈高水平表达,通过检测PDECGF/TP和VEGF能够筛选或确诊间质性膀胱炎.

Abstract：

Objective To find out the relationship among the expression of vascular growth factors in patients with interstitial cystitis (IC) and their performance under the cystoscopy as well as the clinical symptoms by detecting the expression of platelet-derived endothelial growth factor/thymine phosphatase (PDECGF/TP) and vascular endothelial growth factor (VEGF). Methods Twelve cases of IC served as the experimental group and 12 cases of type Ⅲ as the control group. The patients in experimental group had bladder mucosa biopsy. The number of mast cells was observed by HE staining. The expression of PDECGF/TP and VEGF and immunohistological score (IHS) were detected by using immunohistochemistry. Results Bladder mucosa hemorrhage points and sheets were observed under water expansion. The number of mast cells existing in the submucosa of the bladder tissue was significantly greater than in control group (P ＜ 0. 05 ). The percentage of PDECGF/TP and VEGF positive cells and IHS in experimental group were significantly higher than in control group (P ＜ 0. 05). Conclusion The expression of PDECGF/TP and VEGF was up-regulated in patients with IC. IC can be screened out or diagnosed by detecting PDECGF/TP and VEGF.     

Different clinical presentation of interstitial cystitis syndrome

Abstract The aim of the study was to examine how interstitial cystitis (IC) initiates its clinical course, which changes as the disease progresses from the initial phase to its full clinical manifestation. Patients diagnosed with IC between 1998 and 2003 in our department were evaluated and reviewed regularly. The exact onset of urinary symptoms was recorded. Diagnosis of IC was made by National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) criteria when clinical suspicion of IC was present. The study group included 30 female patients who were 27–69 years old when diagnosis was made. Mean age was 46.7. Seventy percent of patients had only one symptom at onset. The most frequent initial diagnosis was urinary tract infection (UTI). A condition of recurrent bacterial UTIs, with subsequent persistence of symptoms and negative cultures, could be detected as a harbinger of IC in 60% of our patient group. IC may manifest initially with a single symptom in its early stage, when diagnosis is perhaps less easy, but adequate and effective treatment can still be offered to the patient. Editorial Comment: Recent data suggest interstitial cystitis (IC) is far more prevalent than previously believed. IC can present at any stage in a womans life. Although most women develop symptoms during their 30s, accurate diagnosis is frequently delayed until women are in their 40s. IC patients experience a spectrum of symptom severity ranging from intermittent UTI-like symptoms to severe urgency, frequency, and pelvic pain. Early diagnosis and treatment remains key in minimizing the symptom severity and syndrome progression for most women     

Current guidelines in the management of interstitial cystitis

Interstitial cystitis (IC) is a heterogeneous chronic disease of unknown etiology that impacts a very large number of women. Symptoms are highly variable: patients may suffer from pelvic pain that is exacerbated by bladder filling, and can be associated with a variety of lower urinary tract symptoms including frequency and urgency. Given the varying presentations and severities of corresponding treatment must be tailored to each specific patient. Current American Urological Association (AUA) guidelines separate the IC treatment recommendations into six tiers of increasing invasive therapies. These treatment guidelines begin with education and lifestyle modifications and progress through levels of physical, pharmacological, and ultimately surgical therapies for those that fail the less invasive therapies. The purpose of this review is to outline the recommendations for the treatment of IC and the evidence from which these recommendations arise. Furthermore, we examine the most up to date literature so that we may recognize future directions in the treatment of IC.     

Efficacy of oral doxepin and piroxicam treatment for interstitial cystitis

OBJECTIVE: To establish the efficacy of a multidrug oral treatment with the tricyclic antidepressant agent doxepin and the cyclooxygenase (COX) inhibitor piroxicam in patients with interstitial cystitis (IC), who had failed standard therapy in an open, prospective, nonrandomized study. METHODS: A total of 37 patients diagnosed with IC received 75 mg doxepin and 40 mg piroxicam daily. The treatment was termed DOXCAM. Effectiveness of therapy was assessed with frequency-volume charts, an IC symptom score and with cystometry prior to treatment, 8 weeks after the start and 4 weeks after termination of drug treatment. RESULTS: Medication was not tolerated by five patients. Twenty-six of 32 patients have experienced virtual total remission of symptoms (81%) and six patients had significant relief (19%). DOXCAM treatment resulted in a significant percent decrease in pain (65% versus 21%). Daytime frequency decreased from 17.6+/-5.7 to 11.3+/-3.6 voids while nocturia did not improve significantly. Twenty-three of the 26 patients who became symptom free and four of the six patients who showed significant improvement had a return of symptoms after cessation of therapy. CONCLUSION: It is reasonable to consider oral treatment with DOXCAM in those patients who have failed first-line therapies.     

间质性膀胱炎16例的诊断与治疗

目的探讨间质性膀胱炎(IC)的诊断和治疗方法。方法回顾分析16例IC患者的临床资料,患者主要表现为尿频、尿急、耻骨上疼痛和慢性盆腔疼痛,误诊为慢性膀胱炎、盆腔炎、子宫内膜异位症、膀胱结核及尿道综合征,经手术后病理或膀胱镜检查确诊,其中4例行尿流改道,2例行乙状结肠膀胱成形术,10例行药物治疗。结果4例患者行尿流改道治疗后盆腔疼痛完全消失。2例行膀胱成形术后仍有轻微会阴部不适,膀胱容量大于350 m l,分别随访24,33个月无复发。10例非手术治疗患者O′Leary-Sant间质性膀胱炎症状评分和IC问题评分分别由治疗前的(15.4±4.1)和(9.4±2.7)分,降至治疗后的(4.1±2.1)和(5.1±3.9)分。结论对IC的诊断和鉴别诊断应给予充分重视;及早诊断及多种措施联合治疗,可显著改善IC患者的症状,提高生活质量。     

Experimental autoimmune cystitis in the Lewis rat: a potential animal model for interstitial cystitis

To develop an autoimmune animal model for interstitial cystitis (IC), we injected rats with Freund's adjuvant (CFA) containing bladder homogenate (experimentals) or CFA alone (shams). We observed a doubling of urinary frequency in the experimental animals over the shams (P=0.004) and histopathologic changes (venular congestion) consistent with IC. Statistically significant bladder capacity changes were not found. Mast cell (MC) number was not statistically different between experimentals and controls but the number of MCs from section to adjacent section within the same animal's bladder did vary markedly, indicating that MC counts are not a reliable measure of disease in the rat bladder. Splenocytes cultured from the experimental animals and transferred to naive syngeneic recipients were capable of transferring the urinary frequency changes and vascular congestion while splenocytes from animals which did not develop the condition were without effect. In summary, we have developed an autoimmune model for IC consistent with the clinical features of IC. The features of this model can be transferred to naive syngeneic recipients via adoptive splenocyte transfer. The model will permit us to ask and answer important questions about the pathogenesis and treatment of the human disease.     

Idiopathic sensory urgency and early interstitial cystitis

The sensory aspects of bladder function are not clearly defined, are poorly understood and imperfectly managed. Sensory urgency or bladder hypersensitivity often present with symptoms without an obvious cause (idiopathic sensory urgency). This article reviews the evidence that some of these symptomatic patients are actually suffering from early interstitial cystitis. The implications of such a possibility are discussed and the possible role of detrusor mast-cell infiltration in the genesis of bladder symptoms in women is examined.     

神经调节器永久性植入治疗间质性膀胱炎合并盆底疼痛四例报告

目的探讨间质性膀胱炎合并盆底疼痛进行骶神经电刺激神经调节治疗的疗效。方法2004年11月至2005年12月,采用美国国立糖尿病、消化病和肾病研究所(NIDDK)制定的标准诊断间质性膀胱炎合并盆底疼痛者4例,并接受永久性神经调节器植入。结果4例经永久性神经调节器植入后,分别随访3-8个月,排尿日记24 h平均尿量由治疗前90-110(96．3±9．3)ml升至治疗后的192～212(201．0±9．2)ml,P<0．05),24 h排尿次数由治疗前的15-25(20．3±4．1)次降至7～12(9．8±2．2)次(P<0．05),夜尿次数由治疗前的8～11(9.8±1.5)次降至治疗后3-6 (4．3±1．3)次(P<0．05),排尿疼痛评分由治疗前的7～10(8．8±1．5)分降至治疗后的1～4(1．8±1．5)分(P<0．01);O'Leary-Sant间质性膀胱炎指数评分由治疗前的均为满分(36分)降至治疗后的8 -11(9．3±1．5)分(P<0．01)。膀胱疼痛和盆底疼痛症状明显缓解,尿频症状也明显改善。结论骶神经电刺激神经凋节治疗是治疗间质性膀胱炎合并盆底疼痛有效、安全的治疗手段。     

Increased number of apoptotic endothelial cells in bladder of interstitial cystitis patients

In this study, we aimed to investigate possible abnormality of bladder endothelial cells in interstitial cystitis patients by detecting morphological changes such as apoptosis in bladder endothelial cells. A bladder biopsy specimen was collected from interstitial cystitis patients immediately after hydrodistension therapy. The patients were classified into two groups on the basis of their predominant symptom, one group of patients with bladder pain and another group of patients with urinary urgency. Dissociated cells from the biopsy specimen were analyzed by flow cytometry after staining with Annexin V and an anti-CD105 antibody. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and electron microscopy were performed to confirm morphologic changes indicative of apoptosis. The percentage of Annexin V binding, an early apoptosis marker, was significantly higher in bladder endothelial cells from interstitial cystitis patients with pain [median 24.7% (range 15.1-77.2), n = 20, P < 0.01) than that from interstitial cystitis patients with urinary urgency [9.3% (range 0.7-19.11) n = 17) or control patients [1.5% (range 0.8-9.1), n = 7]. TUNEL staining showed apoptotic cells in microvascular endothelial cells but not in the endothelial cells of a venule. By electron microscopy, endothelial cells showed morphological changes indicative of apoptosis such as nuclear fragmentation. Our results indicate that increased apoptosis of bladder microvascular endothelial cells may play an important role in the pathogenesis of interstitial cystitis accompanied by bladder pain.     

Resiniferatoxin in the treatment of interstitial cystitis: a systematic review

Resiniferatoxin, a treatment based on a physiopathological concept (the involvement of C fibers and transient receptor potential vanilloid 1 in the transmission of pain) is undergoing evaluation for interstitial cystitis. We evaluated the current evidence from relevant studies identified in PubMed and Scopus databases. Six studies provided contradictory results regarding the effectiveness of resiniferatoxin treatment. The largest study showed no improvement of overall symptoms following a single administration of resiniferatoxin. Three other articles that studied the effectiveness of a single dose of resiniferatoxin gave contradictory results. However, the other two studies, those that examined the effect of multiple or prolonged administration schemes, gave more encouraging results. The use of the regimen is generally well tolerated although mild adverse events such as increase of bladder pain during instillation were sometimes reported by patients and serious adverse events rarely occur. In conclusion, the effectiveness of resiniferatoxin in the treatment of interstitial cystitis remains unknown.     

Depression, abuse and its relationship to interstitial cystitis

This study evaluated the prevalence of depression, sexual abuse, and physical abuse among women diagnosed with interstitial cystitis (IC). One hundred forty-one subjects completed the validated Beck's Depression Inventory II Questionnaire (BDI-II) and the validated Drossman Abuse Questionnaire. Ninety-seven (69%) subjects scored 14 or higher on the BDI-II, corresponding to depression. When compared to the US prevalence of 9%, this was significantly higher. Fifty-one subjects (36%) reported sexual abuse which is higher than the US average. The prevalence of childhood sexual abuse in the sample was not significantly different than the US average. The prevalence of physical abuse in the sample was not statistically different than the US average. Women with IC appear to have a higher prevalence of depression and sexual abuse than the general population. Women with IC should be screened for depression and abuse and referred to a mental health expert as necessary for treatment.     

A survey on clinical practice of interstitial cystitis in Japan

Background

To explore the real-life practice of clinical management of interstitial cystitis (IC) in Japan.

Methods

A questionnaire on the number of IC patients, cystoscopic findings, diagnostic methods, and the treatment modalities was sent via e-mail to 114 medical institutions belonging to the Society of Interstitial Cystitis of Japan (SICJ).

Results

Completed questionnaires were returned from 62 institutions (20 university hospitals, 26 general hospitals and 16 clinics), with a response rate of 54%. The median of patient number per institution was 20 and the national number of IC patients was counted as 4,531 in Japan. The number of new patients in 2013 was 7 (median) per institution and calculated as 1,214 in total. The case volume per institution distributed broadly and skewed to a lower volume. The patients were categorized according to cystoscopic findings as either Hunner type IC with Hunner lesions (n=2,066, 45%), non-Hunner type IC with glomerulations on hydrodistension (n=1,720, 38%) or hypersensitive bladder without endoscopic abnormalities (n=304, 7%), excluding unknown (n=441, 10%). The proportion of Hunner type IC was highly variable among the institutions, ranging from 0% to 100% with a median of 29%. As for evaluation, symptom and quality of life (QOL) assessment by questionnaires, frequency volume chart, urinalysis, urine cytology, urine culture, post-void residual measurement, uroflowmetry, ultrasound and cystoscopy were widely adapted. Administration of oral medicines and intravesical instillation therapy were undertaken at 98% and 63% of institutions, respectively. Hydrodistension was commonly performed, totaling in 812 procedures at 53 institutions, while only five cystectomies were reported from four institutions.

Conclusions

The survey estimated about 4,500 IC patients and 2,000 Hunner type IC patients in Japan. It also revealed a wide range of case volume, acceptable adherence to clinical guidelines, and high variability in the proportion of Hunner type IC. The variable proportions of Hunner type IC despite a high performing rate of endoscopy suggest inconsistency in diagnostic criteria for the Hunner lesion.