Interstitial Cystitis Research Articles

How Intravesical Platelet-Rich Plasma Can Help Patients with Interstitial Cystitis/Bladder Pain Syndrome: A Comprehensive Scoping Review.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition characterized by chronic inflammation that affects the bladder. The study was aimed at evaluating the effectiveness of intravesical platelet-rich plasma (PRP) injections in patients with IC/BPS. We conducted a comprehensive search strategy to involve studies that investigate the efficacy of intravesical PRP injections or instillations over different time intervals. Various outcome measures were assessed, including pain scores, functional outcomes, urodynamic parameters, and surface expressions on the urothelium. Our search strategy revealed 1,125 studies. After screening, ten articles met the inclusion criteria. Intravesical PRP significantly reduced the visual analog scale (VAS) compared with baseline scores. Several clinical trials reported significant improvements in the global response rate (GRA), O'Leary-Sant Symptom (OSS) questionnaire, Interstitial Cystitis Symptom Index (ICSI), and Interstitial Cystitis Problem Index (ICPI). Urodynamic parameters such as maximum flow rate (Qmax) and post-voiding residual (PVR) showed significant improvements in some studies. The study concluded that intravesical PRP injections could be a promising effective treatment option for IC/BPS patients by their significant ability to reduce pain. However, improvement of urodynamic and functional outcomes is still not clear. Further large comparative trials are still warranted to assess the efficacy of PRP instillation.

Effect of Low Intensity Laser Therapy on Painful Bladder Syndrome

Effect of Low Intensity Laser Therapy on Painful Bladder Syndrome

Symptomatic Autonomic Dysfunction in Interstitial Cystitis/Bladder Pain Syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a highly prevalent condition with incompletely understood pathophysiology, especially in relation to the systemic symptoms experienced. The role of autonomic nervous system dysfunction in IC/BPS remains poorly understood. The purpose of this study was to assess the relationship between autonomic symptom severity and clinical characteristics of patients with IC/BPS. This is a retrospective cohort study of 122 IC/BPS patients who completed the Composite Autonomic Symptoms Score (COMPASS-31) questionnaire. Data were collected on anesthetic bladder capacity (BC), Hunner lesion (HL) status, results for validated IC/BPS symptom questionnaires (O'Leary Sant Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index (ICSI/ICPI) and the Pelvic Pain and Urgency/Frequency (PUF) scale), and comorbid nonurologic associated syndromes. Using the first quartile of COMPASS-31 scores as the cutoff, we compared patients within the first quartile (low symptom load; n = 30), to the remainder of the patients (high symptom load; n = 92). Patients scoring ≥20.36 were significantly less likely to be HL positive (10.9% vs 26.7%; P = 0.043) and had a significantly higher BC (823.10 ± 396.07 vs 635.00 ± 335.06; P = 0.027), higher scores on the PUF questionnaire (23.80 ± 4.98 vs; 19.61 ± 5.22 P < 0.001), and a higher number of nonurologic associated syndromes (5.65 ± 2.90 vs 2.60 ± 1.89; P < 0.001). Patients with IC/BPS experience widespread symptoms associated with autonomic nervous system dysfunction. A higher symptom load strongly correlates with a nonbladder-centric phenotype. These findings provide further evidence that total body nervous system dysfunction is present in patients with nonbladder centric IC/BPS.

This pain drives me crazy: Psychiatric symptoms in women with interstitial cystitis/bladder pain syndrome

BACKGROUND Interstitial cystitis/bladder pain syndrome (IC/BPS) is an at least 6-mo noninfectious bladder inflammation of unknown origin characterized by chronic suprapubic, abdominal, and/or pelvic pain. Although the term cystitis suggests an inflammatory or infectious origin, no definite cause has been identified. It occurs in both sexes, but women are twice as much affected. AIM To systematically review evidence of psychiatric/psychological changes in persons with IC/BPS. METHODS Hypothesizing that particular psychological characteristics could underpin IC/BPS, we investigated in three databases the presence of psychiatric symptoms and/or disorders and/or psychological characteristics in patients with IC/BPS using the following strategy: ("interstitial cystitis" OR "bladder pain syndrome") AND ("mood disorder" OR depressive OR antidepressant OR depression OR depressed OR hyperthymic OR mania OR manic OR rapid cyclasterisk OR dysthymiasterisk OR dysphoriasterisk). RESULTS On September 27, 2023, the PubMed search produced 223 articles, CINAHL 62, and the combined PsycLIT/PsycARTICLES/PsycINFO/Psychology and Behavioral Sciences Collection search 36. Search on ClinicalTrials.gov produced 14 studies, of which none had available data. Eligible were peer-reviewed articles reporting psychiatric/psychological symptoms in patients with IC/BPS, i.e. 63 articles spanning from 2000 to October 2023. These studies identified depression and anxiety problems in the IC/BPS population, along with sleep problems and the tendency to catastrophizing. CONCLUSION Psychotherapies targeting catastrophizing and life stress emotional awareness and expression reduced perceived pain in women with IC/BPS. Such concepts should be considered when implementing treatments aimed at reducing IC/BPS-related pain.

The microbiota in patients with interstitial cystitis/bladder pain syndrome: a systematic review.

To comprehensively review and critically assess the literature on microbiota differences between patients with interstitial cystitis (IC)/bladder pain syndrome (BPS) and normal controls and to provide clinical practice guidelines. In this systematic review, we evaluated previous research on microbiota disparities between IC/BPS and normal controls, as well as distinctions among IC/BPS subgroups. A comprehensive literature search was conducted across PubMed/MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials. Relevant studies were shortlisted based on predetermined inclusion and exclusion criteria, followed by quality assessment. The primary focus was identifying specific taxonomic variations among these cohorts. A total of 12 studies met the selection criteria. Discrepancies were adjudicated by a third reviewer. The Newcastle-Ottawa Scale was used to assess study quality. Predominantly, the studies focused on disparities in urine microbiota between IC/BPS patients and normal controls, with one study examining gut microbiota differences between the groups, and two studies exploring vaginal microbiota distinctions. Unfortunately, analyses of discrepancies in other microbiota were limited. Our findings revealed evidence of distinct bacterial abundance variations, particularly involving Lactobacillus, alongside variations in specific metabolites among IC/BPS patients compared to controls. Currently, there is evidence suggesting significant variations in the diversity and species composition of the urinary microbiota between individuals diagnosed with IC/BPS and control groups. In the foreseeable future, urologists should consider urine microbiota dysbiosis as a potential aetiology for IC, with potential clinical implications for diagnosis and treatment.

Unsupervised Machine Learning Reveals a Vulvodynia-Predominant Subtype in Bladder Pain Syndrome/Interstitial Cystitis.

Background Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic condition characterized by pelvic pain and urinary symptoms. Despite its significant impact on patients' quality of life, the heterogeneity of BPS/IC symptoms and the presence of comorbidities such as vulvodynia may not be adequately captured by validated questionnaires. Identifying vulvodynia in BPS/IC patients is crucial for providing appropriate treatment options. This study aimed to identify subtypes of BPS/IC patients using unsupervised machine learning and to investigate the prevalence of vulvodynia in each subtype. Methods We conducted a prospective cross-sectional study of 123 BPS/IC patients and 64 age-matched controls. Hierarchical clustering was performed using data from validated questionnaires, including the Numerical Rating Scale-11, Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Pelvic Pain and Urgency/Frequency scores, Overactive Bladder Questionnaire Short Form (OABq SF), Overactive Bladder Symptom Score (OABSS), and Pelvic Floor Distress Inventory-20. The optimal number of clusters was determined using the elbow method, and the characteristics of each cluster were analyzed. All participants underwent a vulvodynia swab test to assess vulvodynia symptoms. Results Unsupervised machine learning revealed three distinct clusters of BPS/IC patients. Clusters 0 and 2 differed significantly, with Cluster 2 characterized by significantly higher vulvodynia scores compared to other clusters (P < 0.001). In contrast, Cluster 2 had lower bladder pain scores (ICSI and ICPI) and overactive bladder symptom scores (OABq SF and OABSS) compared to other clusters. Clusters 0 and 1 were characterized by a predominance of bladder pain and urinary frequency symptoms, with Cluster 0 exhibiting more severe symptoms. Conclusions Our study identified distinct subtypes of BPS/IC patients using unsupervised machine learning, with Cluster 2 representing a vulvodynia-predominant subtype. This finding, along with the potential of targeted therapies such as non-ablative erbium YAG laser for vulvodynia, underscores the importance of assessing extravesical symptoms, particularly vulvodynia, for the diagnosis and treatment of BPS/IC. A tailored approach, including laser therapy for vulvodynia-predominant patients, may be necessary for optimal management of BPS/IC. The vulvodynia swab test plays a crucial role in assessing vulvodynia symptoms, underlining the limitations of validated questionnaires in capturing the full spectrum of BPS/IC symptoms. A comprehensive evaluation of patients, including the vulvodynia swab test, is essential for accurate subtyping and management of BPS/IC. Further research with larger sample sizes and investigation of the relationship between identified subtypes and other clinical data is warranted to advance our understanding and management of BPS/IC.

(028) IDENTIFYING A CORRELATION BETWEEN EHLERS DANLOS SYNDROME (HYPERMOBILITY TYPE) AND GENITOPELVIC PAIN IN WOMEN

Abstract Introduction Hypermobility Ehlers Danlos Syndrome (hEDS) is the most common subtype of The Ehlers Danlos Syndromes (EDS), a group of heritable connective tissue disorders. Signs and symptoms associated with hEDS include joint hypermobility, joint pain, back/neck pain, easy bruising, soft/velvety skin, stretchy skin, sensitive skin, allergies/hives, gastrointestinal symptoms, dizziness, dysautonomia, hernias, prolapse, and atrophic scaring. Patients with hEDS often display myofascial pain related to muscle overactivity, which may compensate for joint laxity. hEDS is strongly associated with mast cell activation syndrome (MCAS) and postural orthostatic tachycardia syndrome (POTS). Severity of the symptoms associated with hEDS falls on a spectrum. Patients who do not meet full diagnostic criteria for hEDS may still be diagnosed with hypermobile spectrum disorder (HSD). The 5-Point Hypermobility Questionnaire (5HQ) was designed to screen for HSD (1). A score of 2 or more has an 80-85% sensitivity and 80-90% specificity to detect HSD. As the molecular basis of hEDS is still unknown, the diagnosis of hEDS is made based on a positive diagnosis of HSD and additional criteria outlined in the 2017 International Classification of the EDS. Genitopelvic pain disorders (GPP) such as provoked vestibulodynia (PVD) and bladder pain syndrome (BPS) are highly associated with overactive pelvic floor muscle dysfunction (PFD) and mast cell proliferation/activation. As such, it seems likely that hEDS/HSD may play a role in GPP. Objective The objective of this study was to utilize the 5HQ to determine if there is a correlation between GPP and hEDS/HSD. Methods Adult female patients presenting to two clinics specializing in GPP between February 15th, 2023, to October 31st, 2023, prospectively completed the 5HQ. Patients presenting for complaints of a vulvar dermatoses were excluded from the analysis. If a patient screened positive on the 5HQ, a chart review was performed to obtain GPP diagnoses, including vestibulodynia (PVD), overactive pelvic floor muscle dysfunction (PFD), pudendal neuralgia (PN), bladder pain syndrome (BPS), vulvar candidiasis, and desquamative inflammatory vaginitis (DIV). Results Of the 234 patients who met inclusion criteria, 74 screened positive on the 5HQ (31.6%). Of the 74 patients, 73 had vestibulodynia (98.6%), 67 (90.5%) were diagnosed with PFD, 21 (28.4%) had PN, 16 had (probable) BPS (21.6.%), 13 (17.6%) had candidiasis, and 9 (12.2%) had DIV. Of the women with vestibulodynia 26 (35.1%) had allodynia confined to the posterior vestibule suggesting a PFD etiology and 47 (63.5%) had pain throughout their entire vestibule suggesting either an inflammatory or neuroproliferative etiology. Conclusions Nearly one-third of women with GPP screen positive for hESD/HSD. It is possible that myofascial sequelae of hEDS/HSD and MCAS may play a role in women with both GPP and hEDS/HSD. These results highlight the importance of screening women for joint hypermobility who present with GPP. Positive screening should warrant an examination and testing to rule in/out the diagnosis of hEDS and to guide appropriate referral to a specialist in this disorder. Further studies are planned to perform confirmatory diagnosis for hEDS and further explore associated medical conditions, such as MCAS, which may also contribute to forms of GPP. Reference: 1. Hakim AJ, Grahame R. 2003 Int J Clin Pract 57:163-166. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Dare bioscience, Incyte, Nuvig, AbbVie.

The Efficacy of CO2 Vaginal Laser in the Treatment of Recurrent, Post-Coital and Interstitial Cystitis: A Multicentric Prospective Study

Background: This multicentric prospective study was carried out at Fondazione Policlinico Universitario Campus Bio Medico and Ospedale di Stato of St. Marino Republic. Between 1 January 2019, and 31 December 2022, all pre- and post-menopausal women diagnosed with recurrent, post-coital, and interstitial cystitis at both centers were included in the study. The main aim of the study was to assess the effectiveness of vaginal CO2 laser treatment, alone or combined with intravesical hyaluronic acid instillations, in managing cystitis symptoms, such as dysuria, pollakiuria, and urgency, across the entire patient cohort. The secondary objective was to investigate the reduction in number of annual cystitis episodes post-treatment. Methods: Each woman underwent three to four sessions of micro-ablative CO2 vaginal laser treatment. A follow-up examination was conducted 12 months after the final laser session (up to December 2023), during which a post-treatment VAS assessment evaluated dysuria, daily pollakiuria, and urgency. The enrolled patients recorded the number of cystitis episodes experienced during the 12-month pre- and post-treatment period. Results: Results indicated the laser’s efficacy in reducing the total number of cystitis episodes per year and an improvement in symptoms up to one year post-treatment. Greater efficacy of the CO2 laser treatment, particularly when combined with intravesical hyaluronic acid instillation, was observed in both pre- and post- menopausal women. Conclusions: Fractional CO2 laser therapy represents a safe and efficacious, non-hormonal approach for pre- and post-menopausal women diagnosed with recurrent, post-coital, and interstitial cystitis.

(130) PREVALENCE OF CONDITIONS INVOLVING ABERRANT MAST CELL ACTIVITY IN PATIENTS WITH NEUROPROLIFERATIVE VESTIBULODYNIA

Abstract Introduction Neuroproliferative vestibulodynia (NPV) is a provoked vestibular pain shown to be associated with excess immunohistochemical staining for CD117 and PGP9.5, consistent with mast cells and nerves, respectively. NPV is distinguished from control tissue by having &amp;gt;8 mast cells/high power field. Objective In patients with a histopathologically confirmed diagnosis of NPV, we wished to assess the prevalence of concomitant conditions involving other aberrant mast cell activity. Methods Medical records from people with vulvas who underwent vestibulectomy between June 1, 2019 and October 31, 2023 at a single facility were retrospectively reviewed. All had histopathologically confirmed NPV, having observed &amp;gt; 8 positive CD117 stained cells/high power field in the sub-epithelial stroma. As part of their history, each patient provided a list of medical conditions which included disorders where aberrant mast cell activity has been reported. The following eight conditions were included in medical history forms: asthma, chronic sinusitis, endometriosis, food allergy/intolerance, interstitial cystitis, irritable bowel syndrome, migraine, and postural orthostatic tachycardia syndrome. Results A total of 88 NPV patients were included in this chart review. A total of 34 (39%) reported no other aberrant mast cell activity, however 54 (61%) had at least one concomitant condition. The most common conditions were migraine (n=21; 24%), interstitial cystitis (n=17; 19%) and endometriosis (n=15; 17%), followed by food allergy/intolerance (n=12; 14%), irritable bowel syndrome (n=9; 10%), asthma (n=9; 10%), chronic sinusitis (n=5; 6%) and postural orthostatic tachycardia syndrome (n=2; 2%). Among these 88 patients, a total of 33 (38%), 13 (15%), 3 (6%), 1 (1%) and 2 (2%) had one, two, three, four and five other conditions involving aberrant mast cell activity, respectively. There was no correlation between the number of concomitant conditions with aberrant mast cell activity reported and the density of CD117-immunopositive staining in the overall NPV cohort, whether diagnosed with lifelong or acquired NPV. Conclusions Patients with histopathologically confirmed NPV have a high prevalence of concomitant conditions associated with aberrant mast cell activity, possibly due to a genetic predisposition. While more studies are needed, NPV is likely part of a broader systemic collection of conditions associated with aberrant mast cell activity. This finding is relevant in terms of future diagnostic and treatment options for patients with NPV. Disclosure No.

(132) MICONAZOLE VAGINAL CREAM AND ACQUIRED NEUROPROLIFERATIVE VESTIBULODYNIA

Abstract Introduction The vestibular epithelium is non-keratinized and is thus susceptible to injury from an allergic reaction. Topical pharmaceutical agents applied to the genitals for various medical indications, such as miconazole vaginal cream to treat vaginal yeast infections, may absorb through the non-keratinized vestibular epithelium. Active and inactive ingredients in miconazole vaginal cream include miconazole nitrate, benzoic acid, cetyl alcohol, isopropyl myristate, polysorbate 60, potassium hydroxide, propylene glycol, purified water and stearyl alcohol. Patients without vestibular pain previously have reported applying miconazole vaginal cream to their genitals and immediately experienced excruciating burning that resulted in persistent unrelenting severe pain throughout the vestibule, symptoms consistent with acquired neuroproliferative vestibulodynia (NPV). Objective To review reports of clinic patients who used miconazole vaginal cream prior to a diagnosis of acquired NPV to provide awareness of the management of this condition. Methods We performed a chart review of individuals with vulvas presenting to a single sexual medicine clinic between June 2019 and June 2023 to identify those who met the following inclusion criteria. They were clinically suspected to have acquired NPV after an allergic reaction following use of miconazole vaginal cream. They failed conservative treatments for provoked vestibular pain and underwent vestibulectomy. Their excised vestibular specimens revealed an excess of CD117 immunopositive stained cells (&amp;gt;8 per high-power field), consistent with mast cells, and PGP9.5 immunopositive stained area, consistent with nerves, histopathologically confirming the diagnosis of NPV. In addition, demographic data, prior diagnoses and treatments, results from validated questionnaires, pertinent physical exam findings and treatment outcomes were collected. Results A total of 7 individuals met inclusion criteria. Mean age at the time of exposure to miconazole vaginal cream was 23 (range 18-29) years. Mean age at presentation to our sexual medicine facility was 28 (range 22-33) years, thus a delay in diagnosis of miconazole vaginal cream-induced acquired NPV of 5 (range 1-12) years. 71% were previously diagnosed and unsuccessfully managed as hormonally-mediated vestibulodynia and 29% as interstitial cystitis. The mean pain domain score and overall score for the Female Sexual Function Index was 1.2/6 (range 0-3.2/6) and 11.7/36 (range 4.2-18.1/36), respectively. A total score of &amp;lt;26 is indicative of sexual dysfunction. The mean Female Sexual Distress Scale-Revised score was 32.2/52 (range 21-39/52), consistent with significant distress. Conclusions Our cohort of patients with miconazole vaginal cream-induced acquired NPV experienced several years of misdiagnoses, unsuccessful treatments, significant pain, and distress. It is hypothesized that miconazole vaginal cream induces NPV in genetically susceptible individuals in part because the vestibular epithelium is non-keratinized and therefore more easily absorbs the ingredients in the miconazole vaginal cream, which may result in an allergic response in the subepithelial region of the vestibule. This allergic reaction results in accumulation of mast cells in the subepithelial stroma that release nerve growth factor leading to neuroproliferation with subsequent allodynia and hyperalgesia. In individuals who develop yeast infections, use of systemic strategies and rather than topical medication is encouraged to avoid potential allergic reactions and resultant acquired NPV. Disclosure No.

Cdk1/p53/p21 feedback loop mechanisms in the pathogenesis of interstitial cystitis/bladder pain syndrome

PurposeThis study aimed to elucidate the role of the Cdk1/p53/p21 feedback loop in the pathogenesis of interstitial cystitis (IC)/bladder pain syndrome (BPS). Materials and methodsAn IC/BPS cell model was established. Cell viability was determined using the CCK-8 assay. Flow cytometry was adopted to assess cell apoptosis rates. ELISA was employed to measure secretion levels of inflammatory factors (IL-6, IL-8, and TNF-α). Gene expressions were assessed using PCR, while protein expressions were analyzed through Western blotting analysis. Epithelial permeability was demonstrated using the phenol red leakage experiment and FITC-dextran permeability assay. The interaction between proteins was determined using co-immunoprecipitation, and protein localization was investigated using immunofluorescence. ResultsThe CCK-8 assay revealed a significantly reduced viability of IC/BPS cells compared to normal epithelial cells (p < 0.05). Elevated levels of IL-6, IL-8, and TNF-α were detected in IC/BPS cells. Changes in the expressions of E-cadherin and ZO-1 were evident, leading to increased epithelial permeability in IC/BPS cells. Furthermore, within IC/BPS cells, Cdk1 phosphorylated p53 in the nucleus. The Cdk1/p53/p21 feedback loop was established to influence urothelial permeability. Both p21 and Cdk1 inhibitors notably reduced the epithelial permeability in IC/BPS cells. ConclusionThe Cdk1/p53/p21 feedback loop was instrumental in IC/BPS, acting as a regulator of urothelial permeability. This discovery offered a novel therapeutic approach for IC/BPS management.

Intravesical Instillations of Hyaluronic Acid as First-Line Treatment in Patients with Interstitial Cystitis/Bladder Pain Syndrome: Use, Efficacy and Effects on Quality of Life.

The efficacy of hyaluronic acid instillations as therapy for patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) has been demonstrated in some clinical studies, with response rates up to 70%. The aim of the study is to investigate the change in symptoms and quality of life in female patients with IC/BPS after intravesical instillations of hyaluronic acid used as first-line treatment. A retrospective single-center cohort study was conducted. Female patients, whose symptoms were compatible with the diagnosis of IC/BPS as defined by the International Continence Society, were treated with a variable number of intravesical instillations of a hyaluronic acid-based drug. Three validated questionnaires were administered by telephone to all patients, before the beginning of the treatment and 6 months after the last administration of the drug. A total of 50 patients with symptoms compatible with the diagnosis of IC/BPS were included in the study. The median number of instillations performed is 4. For all questionnaires, the median value was significantly reduced following treatment with intravesical instillations (p = 0.000). The present study has shown that intravesical hyaluronic acid treatment results in both statistically and clinically significant symptomatic improvement, thereby improving the quality of life of patients with IC/BPS.

Stem cell therapy for interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease with limited treatment options. Current multidisciplinary approach targeting bladder inflammation and urothelial dysfunction has limited durable effect that major surgery is ultimately required for both Hunner and non-Hunner type IC. Various investigational attempts are underway to avoid such operations and preserve the urinary bladder. Stem cell therapy is a fascinating option for treating chronic illnesses. Stem cells can self-renew, restore damaged tissue, and have paracrine effects. The therapeutic efficacy and safety of stem cell therapy have been demonstrated in numerous preclinical models, primarily chemically induced cystitis rat models. Only one clinical trial (phase 1 study) has investigated the safety of human embryonic stem cell-derived mesenchymal stem cells in three Hunner-type IC patients. Under general anesthesia, participants underwent cystoscopic submucosal stem cell injection (2.0 × 107 stem cells/5 mL). No safety issues were reported up to 12 months of follow-up and long-term follow-up (up to 3 years). Although there were variations in therapeutic response, all patients reported significant improvement in pain at 1 month postoperatively. One patient underwent fulguration of the Hunner lesion after the trial, but others reported an overall improvement in pain. The analysis on phase 1/2a trial which had several modifications in protocol is currently ongoing. Despite several limitations that need to be overcome, stem cell therapy could be a potential therapeutic option for treating IC/BPS. Clinical outcome on phase 1/2a trial is important and might provide more insight into the clinical application of stem cell therapy for IC/BPS.

The Effect of Montelukast on Urinary Symptoms in Children With Bladder Pain Syndrome: A Randomized Clinical Trial.

Montelukast by inhibiting leukotriene receptors in the bladder can prevent the activation of mast cells. We investigated the effectiveness of Montelukast in reducing the symptoms of children with bladder pain syndrome (BPS). In this randomized clinical trial, children were allocated into groups of intervention (Montelukast and oxybutynin) and the control (oxybutynin). At the beginning and after 14 days, questions from mothers of children about their urinary condition were asked about the frequency of nocturnal enuresis, frequent urination, urinary incontinence, urinary urgency, and their pain severity. There was no significant difference between two groups in terms of frequency of nocturnal enuresis, frequent urination, urinary incontinence, and urinary urgency. Regarding the frequency of pain distribution, the frequency of pain-free people in the Montelukast group was higher than control group (84.4% vs 56.3%, P = .023). The results showed that adding Montelukast to oxybutynin has a significant decrease in pain in children with BPS.

A Hypothesis for Anatomical Pathways of Chronic Pelvic Pain of "Unknown Origin".

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disabling bladder condition. ESSIC, the IC/BPS society defines two types of IC/BPS: with Hunner's lesion (HL) and without. Pathogenesis is stated as unknown, with no cure possible. Scheffler in 2021 reported cystoscopically validated cure of HL IC/BPS by repair of uterosacral ligaments (USLs) and in 2022, Goeschen reported non-HL IC/BPS cure in 198 women following USL repair. Both Scheffler and Goeschen hypothesized IC/BPS may be a phenotype of the Integral Theory's Posterior Fornix Syndrome "PFS" (chronic pelvic pain, OAB, and emptying dysfunctions) and therefore potentially curable. The hypothesis explores whether visceral plexuses (VPs), due to weakened USLs support, serve as a primary source of pelvic pain impulses, leading to development of an inflammatory condition - for example, IC/BPS, a chronic inflammatory condition, which shares similarities with vulvodynia and complex regional pain syndrome (CRPS). According to our hypothesis, such conditions involve axon reflexes. Stimuli such as gravity applied to unsupported nerve branches within the visceral pelvic plexus, trigger centrally propagating impulses, which then progress antidromally to influence innervated tissues through cytokine release and nociceptor stimulation, perpetuating inflammatory processes at the end organs, and pain perception. The hypothesis raises the question, "are IC/BPS, vulvodynia, other pain sites, even nonbacterial "chronic prostatitis" in the male, different phenotypes of the chronic pelvic pain syndrome which includes PFS. If so, the hypothesis opens several new research directions and would predict inflammatory findings in tender end organ pain sites.

Intravesical Instillation of Hyaluronic Acid With Epidermal Growth Factor for Restoring Urothelial Denudation and Alleviating Oxidative Stress in Lipopolysaccharide-Induced Interstitial Cystitis of Rats.

To investigate the efficacy of an intravesical instillation of hyaluronic acid (HA) combined with epidermal growth factor (EGF) for the treatment of interstitial cystitis (IC) using a lipopolysaccharide (LPS)-induced IC animal model. A total of 24 female Sprague-Dawley rats were randomized to 4 groups: sham control, IC, HA, and treatment (HA/ EGF) groups. A polyethylene-50 tube was placed inside the bladder of each animal. IC was induced by twice-weekly instillations of LPS for 3 weeks, which resulted in chronic injury of the urothelium. Animals in the sham control group only received saline instillation. Treatment solutions of HA and HA/EGF were given on days 0, 7, and 14 after IC induction (400 μL of HA in a concentration of 0.4 mg/0.5 mL and 400 μL of NewEpi, a commercialized HA/EGF mixture containing 2 μg of EGF and 0.4 mg of sodium hyaluronate). Animals were sacrificed on day 21 for further examinations. The HA/EGF group showed visible improvement in hematuria with a significant reduction of red blood cells in the urine compared to the HA group. Histological examination revealed that HA/EGF treatment reversed the abnormalities developed in IC, including infiltration of inflammatory cells, irregular re-epithelialization, and fibrotic tissue. Moreover, HA/ EGF significantly reduced the levels of proinflammation cytokines (tumor necrosis factor-α, interleukin [IL]-6, and IL-1β) and substantially lowered the elevated oxidative stress biomarker malondialdehyde, yet restored the levels of antioxidant enzymes glutathione peroxidase and superoxide dismutase, with superior results than HA treatment. Cystometry studies indicated that HA/EGF significantly prolonged intercontraction interval and increased micturition volume. HA/EGF has been demonstrated as a more effective treatment for enhancing the urothelium lining and reducing inflammatory changes to alleviate clinical symptoms associated with IC in rats, compared to HA alone.

A Critical Examination of Ligamentous Pathogenesis of Bladder Pain/Lower Urinary Tract Symptoms Using the UEDA Criteria.

To critically analyse the relationship of bladder pain syndrome (BPS/IC), as defined, to the posterior fornix syndrome, "PFS" predictably co-occurring bladder urgency, frequency, nocturia, chronic pelvic pain, emptying symptoms/retention, caused by uterosacral ligament (USL) laxity and cured by USL repair. The starting and end points of this paper are the questions, "Are there arguments that BPS/IC can, in some cases, be linked to PFS?" And if so, "To what extent?" We used the criteria required by Ueda for proper diagnosis: "understanding symptoms, detecting abnormal findings and verifying them as a cause of the symptoms." Literature, diagnostic and surgical, indicate that chronic pelvic pain "of unknown origin" can be caused by unsupported visceral pelvic plexuses because of weak USLs; these cause fire of afferent impulses, which the brain mistakenly interprets as coming from the end-organ itself (i.e., genitourinary pain, lower urinary tract symptoms). The same lax USLs can also weaken the pelvic muscles which contract to stretch the vagina to support the urothelial stretch receptors from below: these may prematurely fire off afferent impulses to activate micturition at lower bladder volumes, interpreted as urgency. A speculum placed in the vagina can relieve pain and urgency by mechanically supporting the vaginal wall and USLs, thus predicting an eventual cure by USL repair. There is need to evaluate what percentage of women with known BPS/IC also pass the criteria for PFS. Identifying a significant percentage of BPS/IC women with the causative relation between PFS pathogenesis and BPS/ IC may open a new way of diagnosing and treating BPS/IC in some women.

Acute Autonomic Nervous System Response to Direct Sacral Nerve Root Stimulation in Lower Urinary Tract Dysfunction: A New Approach to Understand the Mechanism of Action of Sacral Nerve Modulation.

Our goal was to assess acute autonomic nervous system (ANS) response to direct sacral nerve root (SNR) stimulation in the context of lower urinary tract dysfunction. In this retrospective monocentric study, patients undergoing 2-stage sacral nerve modulation for overactive bladder, nonobstructive urinary retention, or chronic bladder pain syndrome between March 2022 and June 2023 were analyzed. A standardized stimulation protocol was applied during the lead implantation, each of the 4 contact points being sequentially stimulated at the amplitude required to elicit anal motor response. Stimulations were labeled as StimA, StimB, StimC, and StimD, ordered by ascending order of minimum amplitude required for anal motor response. Heart rate variability parameters were collected using PhysioDoloris Monitor, and computed through the time-domain (standard deviation of normal-to-normal intervals [SDNN], root mean square of successive differences), the frequency-domain (low frequency, high frequency) and the graphical (Analgesia Nociception Index [ANI]) methods. Fifty patients were analyzed, including 35 females. Twelve patients had an underlying neurological disease. Efficacy was deemed achieved in 54% of patients. SDNN variability significantly increased during StimA to StimC, while maximum SDNN significantly increased only during StimA. ANI variability significantly increased during all 4 stimulations, while maximum ANI significantly increased only during StimA. Direct stimulation of SNR is responsible for a significant increase in ANS and relative parasympathetic nervous system activity, with a greater effect observed when the stimulation was delivered closer to the SNR. These results shed light on potential mechanisms underlying sacral nerve modulation, particularly regarding the treatment of ANS dysregulation in lower urinary tract dysfunction.

Cytokines in Bladder Pain Syndrome: A Review of the Literature.

Bladder pain syndrome (BPS) is poorly understood with both the aetiology and pathophysiology being unknown. Symptoms overlap with other disorders, such as overactive bladder (OAB) and chronic pelvic pain disorders such as endometriosis, making a consensus on how to diagnosis and manage patients challenging. The development of biomarkers for BPS may be the key to understanding more about its pathophysiology, as well as aiding diagnosis, subclassification, and discovering new drug targets for its management. As inflammation is widely understood to hold a central role in BPS, the evaluation of cytokines has gained interest. This article summarises the current literature and understanding of urinary, serum, and bladder tissue cytokines found elevated in patients with bladder pain syndrome. literature search using Pub Med with the keywords "bladder pain syndrome", "painful bladder syndrome", "bladder pain", "Interstitial cystitis" AND "cytokines" or "inflammation". This study was except from institutional approval. Thirty-six cytokines have been identified as being statistically significantly elevated in either the serum, urine, or bladder tissue of patients with bladder pain syndrome in the 22 studies identified in this review of the literature. These cytokines include those from the interleukin group (n = 14), the CXC chemokine group (n = 5), and the C-C chemokine group (n = 7). CXCL-1, CXCL-8, CXCL-9, CXCL-10, CXCL-11 from the CXC chemokine group, and CCL2, CCL4, CCL5, CCL7, and CCL11 from the C-C chemokine group have been found to be significantly elevated in patients with bladder pain in the literature. Many of these analytes also have supporting evidence for their roles in bladder pain from animal models and studies in other chronic inflammatory conditions. It is likely that a single cytokine will not serve as an adequate biomarker of disease in bladder pain syndrome for either diagnosis or disease severity. Instead, panels of inflammatory mediators may reveal more about the different pathways of inflammation leading to similar presentations of bladder pain in patients.

Chemokine receptor 7 contributes to T- and B-cell filtering in ageing bladder, cystitis and bladder cancer

BackgroundResearch has suggested significant correlations among ageing, immune microenvironment, inflammation and tumours. However, the relationships among ageing, immune microenvironment, cystitis and bladder urothelial carcinoma (BLCA) in the bladder have rarely been reported.MethodsBladder single-cell and transcriptomic data from young and old mice were used for immune landscape analysis. Transcriptome, single-cell and The Cancer Genome Atlas Program datasets of BLCA and interstitial cystitis/bladder pain syndrome (IC/BPS) were used to analyse immune cell infiltration and molecular expression. Bladder tissues from mice, IC/BPS and BLCA were collected to validate the results.ResultsEight types of immune cells (macrophages, B-cells, dendritic cells, T-cells, monocytes, natural killer cells, γδ T-cells and ILC2) were identified in the bladder of mice. Aged mice bladder tissues had a significantly higher number of T-cells, γδ T-cells, ILC2 and B-cells than those in the young group (P < 0.05). Three types of T-cells (NK T-cells, γδ T-cells and naïve T-cells) and three types of B-cells (follicular B-cells, plasma and memory B-cells) were identified in aged mice bladder. Chemokine receptor 7 (CCR7) is highly expressed in aged bladder, IC/BPS and BLCA (P < 0.05). CCR7 is likely to be involved in T- and B-cell infiltration in aged bladder, IC/BPS and BLCA. Interestingly, the high CCR7 expression on BLCA cell membranes was a prognostic protective factor.ConclusionsIn this study, we characterised the expression profiles of immune cells in bladder tissues of aged and young mice and demonstrated that CCR7-mediated T- and B-cell filtration contributes to the development of bladder ageing, IC/BPS and BLCA.