Psychosexological correlates of 372 women with vulvodynia, overactive pelvic floor, postcoital cystitis, and interstitial cystitis.

BACKGROUND: Among the plethora of urogynecological conditions possibly affecting women, some of them, less explored, have significant impacts on sexological and psychological health, with a mutual influence. AIM: The aim of this study was to investigate the sexological and psychological correlates of four urogynecological pathologies in a sample of women of childbearing age: overactive pelvic floor, vulvodynia, postcoital cystitis, and interstitial cystitis. Women cured of these conditions were also included, to assess the same aspects after the remission of physical symptoms. METHODS: We recruited 372 women with an average age of 33.5 years through an online platform shared by a popular forum for women with urogynecological pathologies between March and May 2021. The participants filled out a socio-anamnestic questionnaire and a set of psychometric tests. OUTCOMES: Participant data were collected by use of the Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Toronto Alexithymia Scale-20, Female Sexual Function Index, and Orgasmometer-F, and the SPSS (Statistical Package for Social Sciences) v.26 was used for data analysis. RESULTS: Overactive pelvic floor was reported by 66.4% of the women, vulvodynia by 55%, postcoital cystitis by 58.8%, and interstitial cystitis by 8.3%, and these conditions were often comorbid with each other, with 9.4% and 7% of women reporting having suffered psychological and sexual abuse, respectively. The presence of past abuse was correlated with overactive pelvic floor (P < .05), vulvodynia (P < .01), and major depression (P < .01). Significantly more depression occurred in women with vulvodynia than in the other subgroups (P < .05), except for women with only an overactive pelvic floor. There was no difference between the subgroups in the occurrence of alexithymia, sexual function, and orgasm (P < .05). Interestingly, the prevalence of sexual dysfunction increased in cured women. CLINICAL IMPLICATIONS: The lack of significant differences, except for depression, between the pathological subgroups suggests a similar clinical and psychological relevance of the four pathologies studied. The persistence of sexual dysfunctions in cured women may be related to a residual dysfunctional relational modality with the partner. STRENGTHS AND LIMITATIONS: The evaluation of both psychological and sexological variables in a group of less-explored urogynecological conditions represents a strength of this study, while a lack of a face-to-face assessment could represent a limitation. CONCLUSION: The results of the present study should promote psychosexological interventions in women with these diseases, both during the pathological state and after remission.

Latest insights into the pathophysiology of bladder pain syndrome/interstitial cystitis.

PURPOSE OF REVIEW: Bladder pain syndrome/interstitial cystitis (BPS/IC) is a common medical problem in both sexes affecting people of all ages. Patients might report overactive bladder symptoms with additional bladder pain at maximum bladder filling, during and after micturition. This review aims to highlight pathophysiological mechanisms associated with this disease. RECENT FINDINGS: Latest literature exposes different pathophysiological mechanisms such as impaired urothelial barrier function, alteration of urothelial factors and cytokines, chronic inflammation, vascular lesions, neurogenic inflammation and processes in the central nervous system leading to central sensitization. According to the involved mechanisms, BPS/IC may be arranged in clusters according to the clinical phenotype thus helping in clinical decision-making and treatment. Moreover, patients with BPS/IC suffer from other comorbidities such as fibromyalgia, irritable bowel syndrome, chronic pain and functional syndromes and psychosomatic diseases making the management challenging for medical professionals. SUMMARY: Bladder pain syndrome/interstitial cystitis is a complex heterogeneous medical condition involving different pathomechanisms leading to bladder pain and dysfunction, consequently, impairing quality-of-life in affected individuals. However, these mechanisms are still not fully understood, so that patient treatments often remain unsatisfactory. For this reason, continuing research is important to understand the underlying pathomechanisms to discover biomarkers and treatment targets eventually improving diagnostic and therapeutic measures of BPS/IC.

Chronic Overlapping Pain Conditions in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a sample from the Multi-site Clinical Assessment of ME/CFS (MCAM) study.

BACKGROUND: Chronic overlapping pain conditions (COPCs), pain-related conditions that frequently occur together, may occur in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and could impact illness severity. This study aimed to identify comorbid COPCs in patients with ME/CFS and evaluate their impact on illness severity. METHODS: We used data from 923 participants in the Multi-Site Clinical Assessment of ME/CFS study, conducted in seven U.S. specialty clinics between 2012 and 2020, who completed the baseline assessment (595 ME/CFS and 328 healthy controls (HC)). COPCs included chronic low back pain (cLBP), chronic migraine/headache (cMHA), fibromyalgia (FM), interstitial cystitis/irritable bladder (IC/IB), irritable bowel syndrome (IBS), temporomandibular disorder (TMD). Illness severity was assessed through questionnaires measuring symptoms and functioning. Multivariate analysis of variance and analysis of covariance models were used for analyses. Log-binomial regression analyses were used to compute prevalence of COPCs and prevalence ratios (PR) between groups with 95% confidence intervals. Both unadjusted and adjusted results with age and sex are presented. RESULTS: 76% of participants with ME/CFS had at least one COPCs compared to 17.4% of HC. Among ME/CFS participants, cMHA was most prevalent (48.1%), followed by FM (45.0%), cLBP (33.1%), and IBS (31.6%). All individual COPCs, except TMD, were significantly more frequent in females than males. The unadjusted PR (ME/CFS compared to HC) was highest for FM [147.74 (95% confidence interval (CI) = 20.83-1047.75], followed by cLBP [39.45 (12.73-122.27)], and IC/IB [13.78 (1.88-101.24)]. The significance and order did not change after age and sex adjustment. The COPC comorbidities of cLBP and FM each had a significant impact on most health measures, particularly in pain attributes (Cohen's d effect size 0.8 or larger). While the impact of COPC comorbidities on non-pain attributes and quality of life measures was less pronounced than that on pain, statistically significant differences between ME/CFS participants with and without COPCs were still evident. CONCLUSIONS: More than 75% of ME/CFS participants had one or more COPCs. Multiple COPCs further exacerbated illness severity, especially among females with ME/CFS. Assessment and management of COPCs may help improve the health and quality of life for patients with ME/CFS.

EBV infection mediated BDNF expression is associated with bladder inflammation in interstitial cystitis/bladder pain syndrome with Hunner's lesion.

Interstitial cystitis/bladder pain syndrome with Hunner's lesion (HIC) is characterized by chronic inflammation and nerve hyperplasia; however, the pathogenesis of HIC remains a mystery. In this study, we detected both Epstein-Barr virus (EBV) latency infection genes EBNA-1 and LMP-1 and EBV lytic infection BZLF-1 and BRLF-1 expression in the HIC bladders, indicating the coexistence of EBV persistence and reactivation in the B cells in HIC bladders. Upregulation of EBV-associated inflammatory genes in HIC bladders, such as TNF-α and IL-6, suggests EBV infection is implicated in the pathogenesis of bladder inflammation. Nerve hyperplasia and upregulation of brain-derived neurotrophic factor (BDNF) were noted in the HIC bladders. Double immunochemical staining and flow cytometry revealed the origin of BDNF to be EBV-infected B cells. Inducible BDNF expression was noted in B cells upon EBV infection, but not in the T cells. A chromatin immunoprecipitation study revealed BDNF transcription could be promoted by cooperation between EBV nuclear antigens, chromatin modifiers, and B-cell-specific transcription. Knockdown of BDNF in EBV-infected B cells resulted in the inhibition of cell proliferation and viability. Downregulation of phosphorylated SMAD2 and STAT3 after BDNF knockdown may play a role in the mechanism. Implantation of latent EBV-infected B cells into rat bladder walls resulted in a higher expression level of CD45 and PGP9.5, suggesting tissue inflammation and nerve hyperplasia. In contrast, implantation of BDNF depleted EBV-infected B cells abrogated these effects. This is the first study to provide insights into the mechanisms underlying the involvement of EBV-infected B cells in HIC pathogenesis. © 2022 The Pathological Society of Great Britain and Ireland.

Hypertension and urologic chronic pelvic pain syndrome: An analysis of MAPP-I data.

BACKGROUND: Urologic chronic pelvic pain syndrome (UCPPS), which includes interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis (CP/CPPS), is associated with increased voiding frequency, nocturia, and chronic pelvic pain. The cause of these diseases is unknown and likely involves many different mechanisms. Dysregulated renin-angiotensin-aldosterone-system (RAAS) signaling is a potential pathologic mechanism for IC/BPS and CP/CPPS. Many angiotensin receptor downstream signaling factors, including oxidative stress, fibrosis, mast cell recruitment, and increased inflammatory mediators, are present in the bladders of IC/BPS patients and prostates of CP/CPPS patients. Therefore, we aimed to test the hypothesis that UCPPS patients have dysregulated angiotensin signaling, resulting in increased hypertension compared to controls. Secondly, we evaluated symptom severity in patients with and without hypertension and antihypertensive medication use. METHODS: Data from UCPPS patients (n = 424), fibromyalgia or irritable bowel syndrome (positive controls, n = 200), and healthy controls (n = 415) were obtained from the NIDDK Multidisciplinary Approach to the Study of Chronic Pelvic Pain I (MAPP-I). Diagnosis of hypertension, current antihypertensive medications, pain severity, and urinary symptom severity were analyzed using chi-square test and t-test. RESULTS: The combination of diagnosis and antihypertensive medications use was highest in the UCPPS group (n = 74, 18%), followed by positive (n = 34, 17%) and healthy controls (n = 48, 12%, p = 0.04). There were no differences in symptom severity based on hypertension in UCPPS and CP/CPPS; however, IC/BPS had worse ICSI (p = 0.031), AUA-SI (p = 0.04), and BPI pain severity (0.02). Patients (n = 7) with a hypertension diagnosis not on antihypertensive medications reported the greatest severity of pain and urinary symptoms. CONCLUSION: This pattern of findings suggests that there may be a relationship between hypertension and UCPPS. Treating hypertension among these patients may result in reduced pain and symptom severity. Further investigation on the relationship between hypertension, antihypertensive medication use, and UCPPS and the role of angiotensin signaling in UCPPS conditions is needed.

Amniotic bladder therapy: six-month follow up treating interstitial cystitis/bladder pain syndrome.

INTRODUCTION: Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by chronic pelvic pain and usually accompanies lower urinary tract symptoms. We have previously reported that amniotic bladder therapy (ABT) provides symptomatic improvement in refractory IC/BPS patients for up to 3 months. Herein, we evaluated the durability of ABT up to 6 months. MATERIALS AND METHODS: Consecutive IC/BPS patients received intra-detrusor injections of 100 mg micronized amniotic membrane. Clinical evaluation and patient-reported outcome measurements including Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS) and Overactive Bladder Assessment Tool (OAB) were assessed. RESULTS: Twenty-five consecutive recalcitrant IC/BPS patients were included in the study with an average age of 47.4 ± 14.4 years (29-67 years). After ABT, the IC/BPS symptoms improved gradually up to 3 months in all patients with an average improvement in ICSI, ICPI, BPIC-SS and OAB score of 72.8%, 71.9%, and 66.6%, (p < 0.001) respectively, at 3 months. At 4 months after ABT, 7 patients experienced a rebound in symptoms and requested another injection which resulted in a significant improvement in IC/BPS symptoms after 2, 4, and 8 weeks (p < 0.01). For the 18 patients who received only one injection, the IC/BPS symptoms were still significantly lower at 5 and 6 months compared to baseline (p < 0.01), suggesting a possible durable effect based on the ICSI, ICPI, BPIC-SS, and OAB questionnaire scores. CONCLUSIONS: ABT provided an improvement in pain and lower urinary tract symptoms up to 6 months post-treatment in some refractory IC/BPS patients.

Clinically Important Differences for Pain and Urinary Symptoms in Urological Chronic Pelvic Pain Syndrome: A MAPP Network Study.

PURPOSE: Symptom heterogeneity in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively termed urological chronic pelvic pain syndrome, has resulted in difficulty in defining appropriate clinical trial endpoints. We determine clinically important differences for 2 primary symptom measures, pelvic pain severity and urinary symptom severity, and evaluate subgroup differences. MATERIALS AND METHODS: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study enrolled individuals with urological chronic pelvic pain syndrome. We defined clinically important differences by associating changes in pelvic pain severity and urinary symptom severity over 3 to 6 months with marked improvement on a global response assessment using regression and receiver operating characteristic curves. We evaluated clinically important differences for absolute and percent change and examined differences in clinically important differences by sex-diagnosis, presence of Hunner lesions, pain type, pain widespreadness, and baseline symptom severity. RESULTS: An absolute change of -4 was clinically important in pelvic pain severity among all patients, but clinically important difference estimates differed by pain type, presence of Hunner lesions, and baseline severity. Pelvic pain severity clinically important difference estimates for percent change were more consistent across subgroups and ranged from 30% to 57%. The absolute change urinary symptom severity clinically important difference was -3 for female participants and -2 for male participants with chronic prostatitis/chronic pelvic pain syndrome only. Patients with greater baseline severity required larger decreases in symptoms to feel improved. Estimated clinically important differences had lower accuracy among participants with low baseline symptoms. CONCLUSIONS: A reduction of 30%-50% in pelvic pain severity is a clinically meaningful endpoint for future therapeutic trials in urological chronic pelvic pain syndrome. Urinary symptom severity clinically important differences are more appropriately defined separately for male and female participants.

Early and recent exposure to adversity, TLR-4 stimulated inflammation, and diurnal cortisol in women with interstitial cystitis/bladder pain syndrome: A MAPP research network study.

Both early (ELA) and recent life adversity (RLA) have been linked with chronic pain conditions and persistent alterations of neuroendocrine and inflammatory responses. Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic urologic disorder characterized by bladder and/or pelvic pain, and excessive urinary frequency and/or urgency. IC/BPS has been associated with high levels of ELA as well as a distinct inflammatory signature. However, associations between ELA and RLA with inflammatory mechanisms in IC/BPS that might underlie the link between adversity and symptoms have not been examined. Here we investigated ELA and RLA in women with IC/BPS as potential risk factors for inflammatory processes and hypothalamic-pituitaryadrenal (HPA) abnormalities using data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Women with IC/BPS and healthy controls (n = 154 and 32, respectively) completed surveys, collected salivary cortisol at awakening and bedtime for 3 days, and gave a blood sample which was analyzed for 7 LPS-stimulated cytokines and chemokines (IL-6, TNFα, IL-1ß, MIP1α, MCP1, IL-8, and IL-10). Two cytokine/chemokine composites were identified using principal components analysis. Patients with greater exposure to RLA or cumulative ELA and RLA of at least moderate severity showed elevated levels of a composite of all cytokines, adjusting for age, body mass index, and study site. Furthermore, there was a trending relationship between ELA and the pro-inflammatory composite score. Nocturnal cortisol and cortisol slope were not associated with ELA, RLA, or inflammation. The present findings support the importance of adverse events in IC/BPS via a biological mechanism and suggest that ELA and RLA should be assessed as risk factors for inflammation as part of a clinical workup for IC/BPS.

Pelvic mapping to explore patterns of chronic pelvic pain.

PURPOSE: Chronic pelvic pain syndromes (CPPS) are commonly encountered by urologists and urogynecologists and pose diagnostic and therapeutic challenges. Body maps have been helpful adjuncts to verbal descriptions of pain and may serve a role in phenotyping what is known to be a heterogeneous patient population. The aim of this study was to assess whether patterns of pain as marked on a body map of the pelvis exist among common CPPS diagnoses. The secondary aim was to investigate the association between the total number of pain locations marked on the map and clinical indices in patients with 1 to 3 CPPS diagnoses. MATERIALS AND METHODS: Data was collected on patients who visited the Northwell Health Pelvic Pain Treatment Center (PPTC) from January to May 2022 and were diagnosed with at least one of four major CPPS diagnoses: interstitial cystitis/bladder pain syndrome (IC/BPS), pelvic floor myalgia (PFM), chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), and vulvodynia. Demographic data as well as survey data from pelvic pain maps, Genitourinary Pain Index (GUPI) forms, and the short form-6 of the Pain Catastrophizing Scale (PCS-6) were recorded. Descriptive statistics among CPPS groups and Pearson correlations among the number of CPPS diagnoses were computed. RESULTS: One hundred seventy females and 125 males with CPPS were included in the study. Significant cross-over in mapping patterns was notable between IC/BPS and PFM groups, both most commonly marking "abdomen" and "genital" regions. The most distinct pattern of pain was seen in patients with CP/CPPS and in patients with vulvodynia. Among the total sample, as the mean number of pain locations marked within the pelvis increased, GUPI and PCS scores increased (p < 0.05). As the number of CPPS diagnoses increased, the strength of the relationship independently increased. CONCLUSIONS: Pelvic body mapping demonstrated that different forms of CPPS displayed different distributions of pain, but mapping was not predictive of any diagnostic group. Nevertheless, the pelvic body map proved useful in identifying precise locations of pain and may help uncover regions of pain that cannot be easily communicated. The total number of pain sites marked appeared to correlate with worse clinical features.

Temporally complex inflammatory networks in an animal model reveal signatures for interstitial cystitis and bladder pain syndrome phenotype.

INTRODUCTION AND OBJECTIVE: Interstitial cystitis and bladder pain syndrome (IC/BPS) presents with symptoms of debilitating bladder pain and is typically a diagnosis of exclusion. The cystoscopic detection of Hunner's lesions increases the likelihood of detecting tissue inflammation on bladder biopsy and increases the odds of therapeutic success with anti-inflammatory drugs. However, the identification of this subgroup remains challenging with the current lack of surrogate biomarkers of IC/BPS. On the path towards identifying biomarkers of IC/BPS, we modeled the dynamic evolution of inflammation in an experimental IC/BPS rodent model using computational biological network analysis of inflammatory mediators (cytokines and chemokines) released into urine. The use of biological network analysis allows us to identify urinary proteins that could be drivers of inflammation and could therefore serve as therapeutic targets for the treatment of IC/BPS. METHODS: Rats subjected to cyclophosphamide (CYP) injection (150 mg/kg) were used as an experimental model for acute IC/BPS (n = 8). Urine from each void was collected from the rats over a 12-h period and was assayed for 13 inflammatory mediators using Luminex™. Time-interval principal component analysis (TI-PCA) and dynamic network analysis (DyNA), two biological network algorithms, were used to identify biomarkers of inflammation characteristic of IC/BPS over time. RESULTS: Compared to vehicle-treated rats, nearly all inflammatory mediators were elevated significantly (p < 0.05) in the urine of CYP treated rats. TI-PCA highlighted that GRO-KC, IL-5, IL-18, and MCP-1 account for the greatest variance in the inflammatory response. At early time points, DyNA indicated a positive correlation between IL-4 and IL-1ß and between TNF-α and IL-1ß. Analysis of TI-PCA and DyNA at later time points showed the emergence of IL-5, IL-6, and IFNγ as additional key mediators of inflammation. Furthermore, DyNA network complexity rose and fell before peaking at 9.5 h following CYP treatment. This pattern of inflammation may mimic the fluctuating severity of inflammation associated with IC/BPS flares. CONCLUSIONS: Computational analysis of inflammation networks in experimental IC/BPS analysis expands on the previously accepted inflammatory signatures of IC by adding IL-5, IL-18, and MCP-1 to the prior studies implicating IL-6 and GRO as IC/BPS biomarkers. This analysis supports a complex evolution of inflammatory networks suggestive of the rise and fall of inflammation characteristic of IC/BPS flares.

Identification of a potential structure-based GPCR drug for interstitial cystitis/bladder pain syndrome: in silico protein structure analysis and molecular docking.

INTRODUCTION AND HYPOTHESIS: There is currently no effective treatment for interstitial cystitis / bladder pain syndrome (IC/BPS) and thus seriously reduces the quality of life of patients. The purpose of this study is to analyze the structure and function of G protein coupled receptors related to IC/BPS by integrating bioinformatics and provide basis for the development of new drugs for IC/BPS. METHODS: We used ProtParam and DNAMAN to analyze the physical and chemical properties of GPR18 and GPR183 proteins. The secondary and tertiary structure, conservative domain, phosphorylation site of both proteins were predicted by ProtScale, PredictProtein, SWISS-MODEL and GPS5.0 respectively. Multiple sequence alignment of the proteins were carried out by DNAMAN and the phylogenetic tree was constructed by MEGA. Further, the molecular docking verification of cannabidiol and both proteins were carried out by using AutoDock Vin. RESULTS: GPR18 and GPR183 proteins were composed of 331 and 361 amino acids respectively. α-helix is the highest in the secondary structure of the two proteins. Both proteins contain seven transmembrane domains specific to G protein coupled receptors. And homology analysis showed that the two proteins had high homology. In terms of molecular docking, cannabidiol, a non psychoactive component extracted from the cannabis, can form effective molecular binding with GPR18 and GPR183 proteins. CONCLUSIONS: We identified the structures of GPR18 and GPR183 proteins and their highly homologous evolutionary properties. Furthermore, both proteins can form effective binding with cannabidiol which provides new insights for the development of IC/BPS drugs by targeting G protein coupled receptors.

Pentosan polysulfate and a pigmentary maculopathy: causation versus correlation?

INTRODUCTION: Interstitial cystitis (IC) is a chronic disease with urinary tract symptoms and pain. Pentosan polysulfate (PPS) is the only U.S. Food and Drug Administration approved oral medication for the treatment of IC pain and symptoms. Recently, articles described a pigmentary maculopathy in IC patients on long term PPS therapy. Currently, there is no definitive study directly linking PPS as the cause of the pigmentary maculopathy. The aim of this review is to evaluate if PPS is the causative factor of the pigmentary maculopathy or if PPS use is only associated with the pigmentary maculopathy. MATERIALS AND METHODS: A comprehensive review of peer reviewed journals using the search terms IC, maculopathy, mast cells, immune inflammatory components, Tamm-Horsfall protein, cations and tight junctions was performed to examine the pathophysiology and role of chronic inflammation in IC and known retinal maculopathies. RESULTS: Chronic inflammatory cells have been reported in age-related macular degeneration choroid blood vessels and in bladder submucosal and detrusor layers in IC patients. Studies in IC and maculopathies demonstrate a significant milieu of activated chronic inflammatory and immunologic responses that cause a more "leaky" epithelium and a subsequent cascade of inflammatory events that results in the pathological changes seen in these two conditions. CONCLUSIONS: After an analysis of the literature describing a pigmentary maculopathy in IC patients on long term PPS, a causal relationship does not appear to be present. An alternate model is proposed postulating that the causative factor for the pigmentary maculopathy is the underlying inflammatory state associated with IC and not PPS use.

The life experiences of women with interstitial cystitis/bladder pain syndrome: A qualitative phenomenological study.

AIM: To explore the life experiences of women with interstitial cystitis. DESIGN: A qualitative phenomenological study. METHODS: Fifteen women with interstitial cystitis were recruited from a regional hospital in Taiwan using purposive sampling. Data were collected via one-on-one semistructured interviews and analysed using the Colaizzi's method. Rigorous testing was conducted to identify the themes and subthemes. RESULTS: Four major themes were identified: torment, restriction, acceptance and empowerment. These themes reflect the life experiences of women with interstitial cystitis. They endured unrelenting physical and psychological distress and loneliness, experienced obstacles and limitations in daily living because of their symptoms, accepted reality and considered their symptoms as a part of everyday life and developed coping skills for the disease. CONCLUSION: Medical care, psychological support and emotional venting are crucial for women with interstitial cystitis. Despite living a life full of frustrations and suffering caused by the unpredictable and unrelenting nature of interstitial cystitis, through external support and intrinsic positive cognitive reconstruction, women with interstitial cystitis gradually accepted that they were ill. They adapted to their situation, developed a suitable lifestyle and pace and ultimately achieved stable coexistence with the disease. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: Although women with interstitial cystitis are affected by an incurable disease, through adequate assistance and reconstruction of perception, they can develop coping skills and stably coexist with their disease. There is a delicate dynamic balance between their lives and disease. IMPACT: This study may help clinicians to understand patients' life experiences and provide suitable care. This may improve the quality of care provided to women with interstitial cystitis and help them adapt to their disease, thereby improving their life satisfaction. REPORTING METHOD: This study was reported according to the COREQ checklist. PATIENT OR PUBLIC CONTRIBUTION: Women with interstitial cystitis contributed to the study data.

Extracellular vesicles derived from mesenchymal stem cells alleviate neuroinflammation and mechanical allodynia in interstitial cystitis rats by inhibiting NLRP3 inflammasome activation.

BACKGROUND: Neuroinflammation in spinal dorsal horn (SDH) plays an important role in the pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS). Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) exert potent anti-inflammatory activities in the treatment of various diseases. This study aimed to determine the therapeutic effects of MSC-EVs on IC and furtherly investigate the potential mechanism to attenuate neuroinflammation. METHODS: Female IC rat model was established by intraperitoneal injection of cyclophosphamide (50 mg/kg, every 3 days for 3 doses). Inhibition of NLRP3 inflammasome was performed by intraperitoneal injection of MCC950 (10 mg/kg). MSC-EVs were isolated from the culture supernatants of human umbilical cord derived MSCs using ultracentrifugation, and then injected intrathecally into IC rats (20 µg in 10 µl PBS, every other day for 3 doses). Suprapubic mechanical allodynia was assessed using up-down method with von Frey filaments, and micturition frequency was examined by urodynamics. The expression of NLRP3 inflammasome components (NLRP3 and Caspase-1), glial cell markers (IBA-1 and GFAP), proinflammatory cytokines (TNF-α, IL-1ß, IL-6 and IL-18) and TLR4/NF-κB signal pathway (TLR4, p65 NK-κB and phospho-p65 NK-κB) in L6-S1 SDH was measured by Western blot analysis. The cellular localization of NLRP3 in SDH was detected using immunofluorescence co-staining. RESULTS: NLRP3 inflammasome was activated in neurons in SDH of IC rats. NLRP3 inflammasome activation contributed to activation of glial cells and process of spinal neuroinflammation in IC rats, and was related to suprapubic mechanical allodynia and frequent micturition. Intrathecal injection of MSC-EVs alleviated suprapubic mechanical allodynia and frequent micturition in IC rats, restrained activation of glial cells and attenuated neuroinflammation in SDH. In addition, MSC-EV treatment significantly inhibited activation of both NLRP3 inflammasomes and TLR4/NF-κB signal pathway. CONCLUSIONS: NLRP3 inflammasome activation is involved in the neuroinflammation of IC. Intrathecal injection of MSC-EVs alleviates neuroinflammation and mechanical allodynia in IC by inhibiting the activation of NLRP3 inflammasome, and TLR4/NF-κB signal pathway may be the potential regulatory target.

Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome.

PURPOSE: This guideline provides direction to clinicians and patients regarding how to recognize interstitial cystitis/bladder pain syndrome (IC/BPS), conduct a valid diagnostic process, and approach treatment with the goals of maximizing symptom control and patient quality of life while minimizing adverse events and patient burden. METHODS: An initial systematic review of the literature using the MEDLINE® database (search dates 1/1/83-7/22/09) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of IC/BPS. The review yielded an evidence base of 86 treatment articles after application of inclusion/exclusion criteria. In July 2013, the Guideline underwent an Update Literature Review, a process in which an additional literature search is conducted and a systematic review is produced in order to maintain guideline currency with newly published literature. The 2013 review identified an additional 31 articles relevant to treatment. An Update Literature Review in 2022 (search dates: 06/2013-01/2021) identified 63 studies, 53 of which were added to the evidence base. RESULTS: In contrast to the prior versions, the 2022 updated Guideline no longer divides treatments into first-line through sixth-line tiers. Instead, treatment is categorized into behavioral/non-pharmacologic, oral medicines, bladder instillations, procedures, and major surgery. This approach reinforces that the clinical approach for IC/BPS needs to be individualized and based on the unique characteristics of each patient. In addition, new statements were written to provide guidance on cystoscopy for patients with Hunner lesions, shared decision-making, and potential adverse events from pentosan polysulfate. The supporting text on major surgery also has been completely revised. CONCLUSION: IC/BPS is a heterogeneous clinical syndrome. Even though patients present with similar symptoms of bladder/pelvic pain and pressure/discomfort associated with urinary frequency and strong urge to urinate, there are subgroups or phenotypes within IC/BPS. Except for patients with Hunner lesions, initial treatment should typically be nonsurgical. Concurrent, multi-modal therapies may be offered.

Is Pelvic Floor Muscle Tenderness a Distinct Urologic Chronic Pelvic Pain Syndrome Phenotype? Findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Symptom Pattern Study.

PURPOSE: Of women with interstitial cystitis/bladder pain syndrome and men with chronic prostatitis/chronic pelvic pain syndrome 85% have concomitant pelvic floor muscle tenderness (PFT). The significance of this finding is incompletely understood. This study examines PFT among participants in the MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Research Network and its relationship with urologic chronic pelvic pain syndrome (UCPPS) symptom severity in order to determine whether this is a phenotypic predictor in UCPPS. MATERIALS AND METHODS: Participants in the MAPP Network Symptom Patterns Study underwent a standardized pelvic examination (PEX). Trained examiners palpated 6 locations evaluating the pelvic musculature for PFT. Participants were assigned a 0 to 6 PEX score based on the number of areas with tenderness on PEX. Using regression tree models, PEX scores were divided into low (0, 1), mid (2, 3, 4, 5) and high (6). The relationship between PFT and UCPPS symptoms was examined using several validated questionnaires. RESULTS: The study cohort consisted of 562 UCCPS participants (375 females and 187 males) and 69 controls. Diagnoses included interstitial cystitis/bladder pain syndrome (397), chronic prostatitis/chronic pelvic pain syndrome (122), both (34) or no diagnosis (9). Of UCPPS participants 81% had PFT on PEX compared to 9% of controls: 107 (19%) low, 312 (56%) mid and 143 (25%) high. Participants with higher PFT scores had more severe disease burden (worse pelvic pain and urinary symptoms), worse quality of life and more widespread distribution of nonpelvic pain. CONCLUSIONS: UCPPS patients with more widespread PFT have severe pain and urinary symptoms, worse quality of life and a more centralized pain phenotype.

Reliability and Validity of Pain and Urinary Symptom Severity Assessment in Urological Chronic Pelvic Pain: A MAPP Network Analysis.

PURPOSE: We assessed the reliability and validity of an efficient severity assessment for pelvic pain and urinary symptoms in urological chronic pelvic pain syndrome, which consists of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: A total of 578 patients were assessed using brief, empirically derived self-report scales for pelvic pain severity (PPS) and urinary symptom severity (USS) 4 times during a 1-month period and baseline clinic visit that included urological, pain and illness-impact measures. Mild, moderate and severe categories on each dimension were examined for measurement stability and construct validity. RESULTS: PPS and USS severity categories had adequate reliability and both discriminant validity (differential relationships with specific clinical and self-report measures) and convergent validity (common association with nonurological somatic symptoms). For example, increasing PPS was associated with pelvic tenderness and widespread pelvic pain, whereas USS was associated with urgency during a bladder filling test and increased sensory sensitivity. PPS and USS categories were independently associated with nonurological pain and emotional distress. A descriptive analysis identified higher likelihood characteristics associated with having moderate to severe PPS or USS or both. Lack of sex interactions indicated that the measures are comparable in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. CONCLUSIONS: Women and men with urological chronic pelvic pain syndrome can be reliably subgrouped using brief self-report measures of mild, moderate or severe pelvic pain and urinary symptoms. Comparisons with a broad range of clinical variables demonstrate the validity and potential clinical utility of these classifications, including use in clinical trials, health services and biological research.

Predictors of Male Sexual Dysfunction in Urologic Chronic Pelvic Pain Syndrome (UCPPS), Other Chronic Pain Syndromes, and Healthy Controls in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.

BACKGROUND: Sexual dysfunction (SD), including erectile (ED) and ejaculatory dysfunction, is associated with diminished quality of life (QoL) in men with UCPPS (chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and/or interstitial cystitis/bladder pain syndrome (IC/BPS)). AIM: We sought to compare SD among male patients with UCPPS, other chronic pain conditions (positive controls, PC), and healthy controls (HC) without chronic pain, and to evaluate the association of comorbidities, psychosocial factors, and urologic factors of SD in all 3 groups. METHODS: Baseline data from male UCPPS participants, PC (irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia) and HC enrolled in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Epidemiology and Phenotyping Study were included in the analysis. Sexual function was assessed using the International Index of Erectile Function-Erectile Function Domain (IIEFEF) and Ejaculatory Function Scale (EFS). Male ED was defined as a composite IIEF-EF score <21. Higher EFS score indicated worse sexual dysfunction; no threshold to define SD was identified for the EFS. Multivariable logistic and linear regression was used to investigate associations of comorbidities, psychosocial factors, and urologic factors with ED and ejaculatory, respectively. OUTCOMES: Comorbidities, genital pain, and psychosocial factors are associated with SD across the study population and male patients with UCPPS had a high prevalence of ED and greater ejaculatory dysfunction. RESULTS: There were 191 males with UCPPS; 44 PC; and 182 HC. Males with UCPPS had worse SD compared to PC and HC including lower mean IIEF-EF scores, greater degree of ejaculatory dysfunction, and lower quality of sexual relationships. Among all 3 cohorts, depression, stress, and pain were associated with ED in univariable and multivariable analysis, as was diabetes mellitus. Pain in the genitalia, severity of urinary symptoms, depression, stress, and history of childhood sexual trauma were associated with ejaculatory dysfunction in univariable and multivariable analysis. CLINICAL IMPLICATIONS: A multidisciplinary approach that addresses the identified risk factors for SD may improve overall QoL in males with UCPPS. STRENGTHS AND LIMITATIONS: Our study is strengthened by its use of validated, patient-reported questionnaires and inclusion of healthy and positive controls. Our understanding of the role of IC in this study is limited because only 1 patient in the study had IC/BPS as a sole diagnosis. CONCLUSIONS: When compared to healthy controls and patients with other chronic pain conditions, males with UCPPS experience higher degrees of SD, including erectile and ejaculatory dysfunction. Loh-Doyle JC, Stephens-Shields AJ, Rolston R, et al. Predictors of Male Sexual Dysfunction in Urologic Chronic Pelvic Pain Syndrome (UCPPS), Other Chronic Pain Syndromes, and Healthy Controls in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. J Sex Med 2022;19:1804-1812.

Prospective randomized controlled trial comparing fulguration versus fulguration and hydrodistension for Hunner-type interstitial cystitis/bladder pain syndrome.

PURPOSE: In Hunner-type interstitial cystitis/bladder pain syndrome (IC/BPS), it is unclear whether suburothelial afferents underlying normal-appearing background areas contribute to symptom development. We examined whether adding hydrodistension (HD) to transurethral fulguration (TUF) of Hunner lesions, for the purpose of treating the background areas, is superior to TUF alone. METHODS: This randomized controlled trial included 52 patients with Hunner-type IC/BPS allocated at a 1:1 (TUF:TUF+HD) ratio. HD was performed at 80 cmH2O for 8 min before TUF in the TUF+HD group. Thirty-three patients remained until the end of the 6-month observational period. The primary endpoint was the visual analogue scale (VAS) pain score at 1 month. Major secondary endpoints were the treatment-failure rate, VAS pain scores at ≥ 2 months, and frequency-volume chart parameters. RESULTS: Both TUF and TUF+HD showed significant improvement in VAS pain score at 1 month (95% confidence interval [CI]: - 1.62 to 0.16, P = 0.106). VAS pain scores were significantly lower in TUF+HD than TUF at 2 (95% CI: - 1.97 to - 0.28, P = 0.011), 4 (95% CI: - 2.83 to - 0.72, P = 0.002), and 6 (95% CI: - 3.11 to - 0.07, P = 0.040) months. Treatment-failure rate was higher in TUF (36.4%) than TUF+HD (17.4%), without significance (odds ratio: 2.714, 95% CI: 0.68 to 10.84, P = 0.189). Functional capacity and urgency were not significantly different between groups. CONCLUSION: The addition of HD to TUF tended to be superior to TUF monotherapy for controlling pain in Hunner-type IC/BPS. This indicates that not only Hunner lesions but also normal-appearing background areas may have a role in the pain of IC/BPS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03987594, date of registration: 2019-06-17 (retrospectively registered).

Pathophysiology, assessment, and treatment of overactive bladder symptoms in patients with interstitial cystitis/bladder pain syndrome.

INTRODUCTION: Interstitial cystitis/bladder pain syndrome (IC/BPS) is prevalent, difficult to treat, and has close symptom overlap with overactive bladder (OAB). A review of the pathophysiology, assessment, and treatment of IC/BPS patients with overlapping OAB symptoms has not been summarized recently in the published literature. METHODS: A review of the published literature on the overlap of IC/BPS and OAB was conducted using MeSH terminology (1992-2022). RESULTS: The pathophysiology of IC/BPS is not fully understood. Animal research has found the bladder trigone and base are richly populated by afferent fibers, including many small unmyelinated C-fibers that may be upregulated in IC/BPS. Successful therapies with multimodal effects on OAB symptoms in patients with IC/BPS are likely to exert beneficial effects on both pain and lower urinary tract symptoms. Potentially efficacious therapies for the treatment of OAB in IC/BPS include pelvic floor physical therapy, oral pharmacotherapy (antimuscarinics and beta-3 agonists), sacral neuromodulation, percutaneous tibial nerve stimulation, and botulinum toxin A (BTA). Antimuscarinics and beta-3 agonists have yielded partial efficacy in IC/BPS, although may help differentiate symptoms of OAB from those associated with IC/BPS. The transvaginal trigone treatment (T3) intradetrusor injection approach allows for delivery of therapeutics to the bladder without the need for a cystoscope and appears to be feasible. CONCLUSIONS: Further research is needed to understand the pathophysiology of IC/BPS and symptom overlap with OAB, which in turn should enable the development of more personalized therapeutics.