Blood vessel occlusion by Cryptococcus neoformans is a mechanism for haemorrhagic dissemination of infection.

Meningitis caused by infectious pathogens is associated with vessel damage and infarct formation, however the physiological cause is often unknown. Cryptococcus neoformans is a human fungal pathogen and causative agent of cryptococcal meningitis, where vascular events are observed in up to 30% of patients, predominantly in severe infection. Therefore, we aimed to investigate how infection may lead to vessel damage and associated pathogen dissemination using a zebrafish model that permitted noninvasive in vivo imaging. We find that cryptococcal cells become trapped within the vasculature (dependent on their size) and proliferate there resulting in vasodilation. Localised cryptococcal growth, originating from a small number of cryptococcal cells in the vasculature was associated with sites of dissemination and simultaneously with loss of blood vessel integrity. Using a cell-cell junction tension reporter we identified dissemination from intact blood vessels and where vessel rupture occurred. Finally, we manipulated blood vessel tension via cell junctions and found increased tension resulted in increased dissemination. Our data suggest that global vascular vasodilation occurs following infection, resulting in increased vessel tension which subsequently increases dissemination events, representing a positive feedback loop. Thus, we identify a mechanism for blood vessel damage during cryptococcal infection that may represent a cause of vascular damage and cortical infarction during cryptococcal meningitis.

Detection of Bacteria in Bladder Mucosa of Adult Females.

PURPOSE: Interstitial cystitis/bladder pain syndrome is a chronic urological condition diagnosed in nearly 8 million females in the United States. Whether urinary microbiota play an etiological role remains controversial. Most studies assessed the microbiota of interstitial cystitis/bladder pain syndrome patients with voided or catheterized urine as a proxy for bladder urothelium; however, urine may not be a true reflection of the bladder microbiota. Bladder biopsy tissue may provide a more accurate, and thus more clinically relevant, picture of bladder microbiota. MATERIALS AND METHODS: Bladder biopsy tissues were obtained from: (1) 30 females with interstitial cystitis/bladder pain syndrome (18-80 years old) via cystoscopically guided cold-cup biopsy following therapeutic bladder hydrodistention, and (2) 10 non-interstitial cystitis/bladder pain syndrome females undergoing pelvic organ prolapse repair. To detect bacteria, technical duplicates of each RNAlater-preserved biopsy were subjected to 16S rRNA gene sequencing. To visualize bacteria, paraformaldehyde-fixed, paraffin-embedded biopsies were subjected to a combined multiplexed fluorescence in situ hybridization and fluorescence immunohistochemistry assay and confocal microscopy. RESULTS: Bacteria were detected by 16S rRNA gene sequencing in at least 1 technical duplicate of most biopsies. The most abundant genus was Staphylococcus, followed by Lactobacillus; Escherichia was common but not abundant. There was no significant difference between interstitial cystitis/bladder pain syndrome patients and controls (P > .05). Combined fluorescence in situ hybridization and immunohistochemistry reproducibly detected 16S rRNA in epithelial cells and shed cells in the urothelium and lesioned areas and capillary walls in the lamina propria of human bladder biopsy tissue. CONCLUSIONS: We conclude that urothelial and urinary microbiota are similar but not identical in adult females.

Re: Pentosan polysulfate and a pigmentary maculopathy: causation versus correlation?

How should a conscientious physician advise patients with Interstitial Cystitis /Bladder Pain Syndrome (IC/BPS) when they want to know if taking Pentosan Polysulfate Sodium (PPS) will lead to loss of vision? Ever since the initial report from Pearce et al in 2018 suggesting that PPS usage can lead to the development of pigmented maculopathy (PM), my patients have been inundated with solicitations from attorneys looking to sign up clients for class action lawsuits.1 While there have been additional reports suggesting a relationship between PPS exposure and the development of PM, Ludwig et al found that there was no difference in the rate of macular disease between patients with documented IC/BPS who had taken PPS and those with IC/BPS with no history of PPS use.2 The large size of Ludwig's study certainly suggests that PPS may not cause PM to develop, and if the rate of PM in the IC population is higher than in controls, it may be due to the disease itself and not from the medication. In this manuscript, Proctor clearly describes the immune inflammatory response that is responsible for the development of the bladder damage seen with IC/BPS. Also, he describes how inflammatory mediators can enter the blood stream and might be a potential cause for the development of PM.3 This is a thought-provoking hypothesis that demands further evaluation. I have prescribed PPS since its approval and have many patients who feel it is an essential part of their IC treatment regimen. There is no other prescription medication that functions in the same fashion. I require them to follow the FDA recommendations for annual eye exams to look for PM development. I also advise patients that as they improve, we will discuss dose reduction and even discontinuation if their IC symptoms have abated. By following these suggestions, one should be able to continue to prescribe PPS for appropriate patients while carefully monitoring them for PM. I found this article extremely informative and will refer to it when counseling patients about IC/BPS and PPS.

Correction: 15-keto-prostaglandin E2 activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promote Cryptococcus neoformans growth during infection.

[This corrects the article DOI: 10.1371/journal.ppat.1007597.].

Pulsed electromagnetic field (PEMF) as an adjunct therapy for pain management in interstitial cystitis/bladder pain syndrome.

INTRODUCTION AND HYPOTHESIS: Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often experience chronic pelvic and even systemic pain that can be difficult to clinically manage. Pulsed electromagnetic field (PEMF) therapy, a non-invasive strategy that has shown significant efficacy for pain reduction in other chronic pain conditions, may provide benefit for pain management in patients with IC/BPS. METHODS: PEMF delivery to patients occurs via a bio-electromagnetic-energy device which consists of a flexible mat (180 × 50 cm) that the patient lies on for systemic, full-body delivery and/or a flexible pad (50 × 15 cm) for targeted delivery to a specific body region (e.g., pelvic area). The duration of individual sessions, number of sessions per day, total number of sessions, and follow-up observation period vary between previously published studies. Positive outcomes are typically reported as a significant reduction in visual analog scale (VAS) pain score and functional improvement assessed using validated questionnaires specific to the condition under study. RESULTS AND CONCLUSIONS: The use of PEMF has been evaluated as a therapeutic strategy for pain management in several clinical scenarios. Randomized, double-blinded, placebo-controlled trials have reported positive efficacy and safety profiles when PEMF was used to treat non-specific low back pain, patellofemoral pain syndrome, chronic post-operative pain, osteoarthritis-related pain, rheumatoid arthritis-related pain, and fibromyalgia-related pain. Based on these positive outcomes in a variety of pain conditions, clinical trials to evaluate whether PEMF can provide a safe, non-invasive therapeutic approach to improve symptoms of chronic pain and fatigue in patients with IC/BPS are warranted.

Functional genomic analyses of IC/BPS patient subgroups: a pilot study.

INTRODUCTION: To further facilitate understanding of disease pathophysiology and patient stratification in interstitial cystitis/bladder pain syndrome (IC/BPS), we utilized molecular phenotyping to compare three clinically distinct IC/BPS patient subgroups. MATERIALS AND METHODS: Total RNA (miRNA and mRNA) was isolated via standard protocols from IC/BPS patient bladder biopsies and assayed on whole genome and microRNA expression arrays. Data from three patient subgroups (n = 4 per group): (1) low bladder capacity (BC; ≤ 400 cc) without Hunner's lesion, (2) low BC with Hunner's lesion, and (3) non-low BC (> 400 cc) were used in comparative analyses to evaluate the influence of BC and HL on gene expression profiles in IC/BPS. RESULTS: The BC comparison (Group 1 v 3) identified 54 miRNAs and 744 mRNAs. Eleven miRNAs mapped to 40 genes. Hierarchical clustering of miRNA revealed two primary clusters: (1) 3/4 low BC patients; (2) 4/4 non-low and 1/4 low BC patients. Clustering of mRNA provided clear separation based on BC. The HL comparison (Group 1 v 2) identified 16 miRNAs and 917 mRNAs. 4 miRNAs mapped to 13 genes. Clustering of miRNA and mRNA revealed clear separation based on HL status. CONCLUSIONS: Significant molecular differences in IC/BPS were found to be associated with the low BC phenotype (e.g., an upregulation of cell proliferation and inflammation marker genes), as well as additional molecular findings that further define the HL+ phenotype (e.g., upregulation of genes involved in bioenergetics reactions) and suggest oxidative stress may play a role.

15-keto-prostaglandin E2 activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promote Cryptococcus neoformans growth during infection.

Cryptococcus neoformans is one of the leading causes of invasive fungal infection in humans worldwide. C. neoformans uses macrophages as a proliferative niche to increase infective burden and avoid immune surveillance. However, the specific mechanisms by which C. neoformans manipulates host immunity to promote its growth during infection remain ill-defined. Here we demonstrate that eicosanoid lipid mediators manipulated and/or produced by C. neoformans play a key role in regulating pathogenesis. C. neoformans is known to secrete several eicosanoids that are highly similar to those found in vertebrate hosts. Using eicosanoid deficient cryptococcal mutants Δplb1 and Δlac1, we demonstrate that prostaglandin E2 is required by C. neoformans for proliferation within macrophages and in vivo during infection. Genetic and pharmacological disruption of host PGE2 synthesis is not required for promotion of cryptococcal growth by eicosanoid production. We find that PGE2 must be dehydrogenated into 15-keto-PGE2 to promote fungal growth, a finding that implicated the host nuclear receptor PPAR-γ. C. neoformans infection of macrophages activates host PPAR-γ and its inhibition is sufficient to abrogate the effect of 15-keto-PGE2 in promoting fungal growth during infection. Thus, we describe the first mechanism of reliance on pathogen-derived eicosanoids in fungal pathogenesis and the specific role of 15-keto-PGE2 and host PPAR-γ in cryptococcosis.

Hydrodistention does not alter bladder gene expression profiles in patients with non-Hunner lesion interstitial cystitis/bladder pain syndrome.

AIMS: Gene expression profiling of bladder biopsies in patients with interstitial cystitis/bladder pain syndrome (IC/BPS), typically obtained following therapeutic bladder hydrodistention (HOD), is used to improve our understanding of molecular phenotypes. The objective of this study was to determine if the HOD procedure itself impacts the biopsy gene expression profile and, by extension, whether biopsies from non-HOD bladders are appropriate controls. METHODS: Bladder biopsies were obtained just before HOD and immediately following HOD from 10 consecutively recruited IC/BPS patients undergoing therapeutic HOD. Biopsies were also obtained from four non-IC/BPS patients who did not undergo HOD (controls). Total RNA was isolated from each of the 24 samples and used to query whole-genome microarrays. Differential gene expression analysis was performed to compare expression profiles of IC/BPS biopsies before and after HOD, and between IC/BPS and control biopsies. RESULTS: Principal component analysis revealed complete separation between gene expression profiles from IC/BPS and control samples (q ≤ 0.05) and while IC/BPS samples before and after HOD showed no significant differences in expressed genes, 68 transcripts were found to be significantly different between IC/BPS and control samples (q ≤ 0.05). CONCLUSIONS: The bladder HOD procedure itself does not significantly change gene expression within the IC/BPS patient bladder, a finding that provides evidence to support the use of biopsies from non-IC/BPS patients that have not undergone HOD as controls for gene expression studies.

Injection location does not impact botulinum toxin A efficacy in interstitial cystitis/bladder pain syndrome patients.

INTRODUCTION: Botulinum toxin A (BTX-A) is currently used as a fourth-line therapeutic option for interstitial cystitis/bladder pain syndrome (IC/BPS) management. The purpose of this study was to determine if BTX-A injection can mitigate pain and if injection location (i.e. trigone-including versus trigone-sparing injection template) impacts treatment efficacy and/or treatment complications profile. MATERIALS AND METHODS: Female IC/BPS patients refractory to conservative management strategies were prospectively enrolled and asked to complete a baseline history and physical exam, post-void residual (PVR) urine volume determination, O'Leary Sant (OLS) questionnaire, and Pelvic Pain and Urgency/Frequency Symptom Scale (PUF) questionnaire. Participants were randomly assigned to one of two treatment groups and received either: 1) a trigone-including BTX-A injection template or 2) a trigone-sparing injection template. Following therapy, patients were examined in clinic at 30 and 90 day post-treatment with symptom re-assessment via repeat questionnaires and for evidence of post-procedural complications. RESULTS: Compared to baseline, patients in both treatment groups experienced significant improvement in OLS and PUF scores at both 30 and 90 days post-treatment with BTX-A, regardless of which injection template was used (p < 0.05). Complications resulting from BTX-A were minimal (most commonly urinary tract infection (UTI) and urinary retention) and not significantly different between the treatment groups (p > 0.05). No distant spread of BTX-A was observed in any patient in either treatment group. CONCLUSIONS: BTX-A treatment using either a trigone-sparing or trigone-including injection template resulted in significant, but not location-dependent, improvement in IC/BPS symptom scores at 30 and 90 day points post-procedure with no significant difference in post-treatment complication profiles.

Non-bladder centric interstitial cystitis/bladder pain syndrome phenotype is significantly associated with co-occurring endometriosis.

INTRODUCTION: Interstitial cystitis/bladder pain syndrome (IC/BPS) and endometriosis are coexistent diagnoses in 48%-65% of women with chronic pelvic pain (CPP), suggesting that dual screening may be warranted. To further investigate the clinical relationship and risk factors between these two conditions, we performed a retrospective review of our large IC/BPS patient data registry. MATERIALS AND METHODS: We evaluated IC/BPS patients who were prospectively enrolled into our registry who completed validated questionnaires and underwent therapeutic hydrodistension, during which anesthetic bladder capacity (BC) and Hunner's lesion (HL) status were recorded. Demographic/medical history were reviewed. IC/BPS patients with co-occurring endometriosis diagnosis versus those without were compared using descriptive statistics as well as multivariate regression analyses to determine predictors of co-occurring disease. RESULTS: Of 431 IC/BPS participants, 82 (19%) were also diagnosed with endometriosis. These women were significantly younger, had increased prevalence of non-low BC (> 400 cc), and decreased prevalence of HL (p < 0.05). Patients with co-occurring endometriosis also had increased prevalence of irritable bowel syndrome (IBS), CPP, fibromyalgia, and vulvodynia (p < 0.05). On multivariate analysis, non-low BC (OR 4.53, CI 1.004-20.42, p = 0.049), CPP (OR 1.84, CI 1.04-3.24, p = 0.04), and fibromyalgia (OR 1.80, CI 1.03-3.14, p < 0.04) were significantly associated with a diagnosis of endometriosis. CONCLUSIONS: Patients with IC/BPS and co-occurring endometriosis were significantly more likely to carry a non-bladder centric IC/BPS phenotype as well as several comorbid, systemic pain diagnoses. This study characterizes features of a target IC/BPS phenotype that could potentially benefit from endometriosis and systemic pain syndrome screening.

Role of urinary cations in the etiology of interstitial cystitis: A multisite study.

OBJECTIVE: To determine whether patients with interstitial cystitis have elevated levels of toxic urinary cations, to identify and quantify these cationic metabolites, and to assess their cytotoxicity. METHODS: Isolation of cationic fraction was achieved by solid phase extraction using an Oasis MCX cartridge on urine specimens from interstitial cystitis patients and controls. C18 reverse phase high-performance liquid chromatography was used to profile cationic metabolites, and they were quantified by the area under the peaks and normalized to creatinine. Major cationic fraction peaks were identified by reverse phase high-performance liquid chromatography and liquid chromatography-mass spectrometry. HTB-4 urothelial cells were used to determine the cytotoxicity of cationic fraction and of individual metabolites. RESULTS: The reverse phase high-performance liquid chromatography analysis was carried out on cationic fraction metabolites isolated from urine samples of 70 interstitial cystitis patients and 34 controls. The mean for controls versus patients was 3.84 (standard error of the mean 0.20) versus 6.71 (0.37) mAU*min/µg creatinine, respectively (P = 0.0001). The cationic fraction cytotoxicity normalized to creatinine for controls versus patients in mean percentage was -7.79% (standard error of the mean 3.32%) versus 20.03% (standard error of the mean 2.75%; P < 0.0005). The major toxic cations were 1-methyladenosine, 1-methylguanine, N2 ,N2 -dimethylguanosine and L-tryptophan. CONCLUSIONS: These data confirm significant elevation of toxic cations in the urine of interstitial cystitis patients. These toxic cations likely represent a primary cause of interstitial cystitis, as they can injure the bladder mucus and initiate an epithelial leak.

Are macrophages the heroes or villains during cryptococcosis?

Cryptococcus infections represents a major healthcare burden, with over 200,000 cases globally a year and even with treatment, mortality remains as high as 80%. There is a clear need for new classes of treatment, especially with the global threat of antifungal resistance. Several groups are investigating the potential of immunotherapy - circumventing many of the issues with current treatments. Macrophages are a cell type known to be heavily associated with cryptococcal infection, from the innate immune response through to the later stage chronic adaptive response - making these an ideal target for manipulation. However, it is currently debated whether macrophage activity is positive or negative for host outcomes. Here, we discuss the current literature surrounding the role of macrophages during Cryptococcus infection, and makes cases for and against macrophage enhancement. Finally, we discuss which pressing questions in the field still remain that require answers in order to safely design an immunotherapeutic with high efficacy.

Small fiber polyneuropathy as a potential therapeutic target in interstitial cystitis/bladder pain syndrome.

INTRODUCTION AND HYPOTHESIS: Interstitial cystitis/bladder pain syndrome (IC/BPS) and fibromyalgia (FM) are frequently co-occurring medical diagnoses in patients referred to the urology clinic for secondary and tertiary treatment options. METHODS: Abundant literature has shown that many patients with FM have small fiber polyneuropathy (SFPN) that can be confirmed via skin punch biopsy and immunological staining to measure nerve density. RESULTS AND CONCLUSIONS: This finding of SFPN provides a therapeutic target for FM and in this article we hypothesize and provide rationale for the idea that this same phenomenon (SFPN) might explain, in some IC/BPS patients, the finding of widespread pain and likewise provide a therapeutic target for these patients.

Histological evidence supports low anesthetic bladder capacity as a marker of a bladder-centric disease subtype in interstitial cystitis/bladder pain syndrome.

INTRODUCTION AND HYPOTHESIS: Low anesthetic bladder capacity has been shown to be a biomarker for bladder-centric interstitial cystitis/bladder pain syndrome (IC/BPS). The goal of this study was to determine if histopathological evidence from bladder biopsies supports anesthetic bladder capacity (BC) as a marker to distinguish a bladder-centric IC/BPS subtype. METHODS: From a review of our large IC/BPS cohort of patients undergoing hydrodistention, we identified a total of 41 patients with low BC (≤ 400 ml); an additional 41 consecutive patients with BC > 400 ml were selected as the comparator group. The original bladder mucosal biopsy pathology slides were re-reviewed by a single pathologist (blinded to patient information) using a standardized grading scale developed for this study. RESULTS: Histologically, the low BC subjects exhibited higher levels of acute inflammation (p = 0.0299), chronic inflammation (p = 0.0139), and erosion on microscopy (p = 0.0155); however, there was no significant difference in mast cell count between groups (p = 0.4431). There was no significant gender difference between the groups; female patients were the majority in both groups (low BC: 94.12%, non-low BC: 100%; p = 0.1246). Individuals in the low BC group were older (p < 0.0001), had a higher incidence of Hunner's lesions on cystoscopy (p < 0.0001), and had significantly higher scores, i.e., more bother symptoms, on two IC/BPS questionnaires (ICPI, p = 0.0154; ICSI, p = 0.0005). CONCLUSIONS: IC/BPS patients with low anesthetic bladder capacity have histological evidence of significantly more acute and chronic inflammation compared with patients with a non-low bladder capacity. These data provide additional evidence to support low bladder capacity as a marker of a distinct bladder-centric IC/BPS phenotype.

Bladder Capacity is a Biomarker for a Bladder Centric versus Systemic Manifestation in Interstitial Cystitis/Bladder Pain Syndrome.

PURPOSE: Interstitial cystitis/bladder pain syndrome presents a significant clinical challenge due to symptom heterogeneity and the myriad associated comorbid medical conditions. We recently reported that diminished bladder capacity may represent a specific interstitial cystitis/bladder pain syndrome subphenotype. The objective of this study was to investigate the relationship between anesthetic bladder capacity, and urological and nonurological clinical findings in a cohort of patients with interstitial cystitis/bladder pain syndrome who had undergone therapeutic urinary bladder hydrodistention. MATERIALS AND METHODS: This is a retrospective chart review of prospectively collected data on women diagnosed with interstitial cystitis/bladder pain syndrome between 2011 and 2015 who underwent bladder hydrodistention. Assessments in each patient included a detailed history and physical examination, ICPI (Interstitial Cystitis Problem Index), ICSI (Interstitial Cystitis Symptom Index) and PUF (Pelvic Pain and Urgency/Frequency Patient Symptom Scale). Bladder capacity was determined during bladder hydrodistention with the patient under general anesthesia. RESULTS: Mean age was 45.8 years and mean bladder capacity was 857 ml in the 110 enrolled patients. We found a significant inverse correlation between bladder capacity and scores on 3 gold standard interstitial cystitis/bladder pain syndrome metrics, including ICPI (p = 0.0014), ICSI (p = 0.0022) and PUF (p = 0.0009) as well as urination frequency (p = 0.0025). Women with higher bladder capacity were significantly more likely to report depression (p = 0.0059) and irritable bowel syndrome (p = 0.022). CONCLUSIONS: Low bladder capacity while under anesthesia was significantly associated with high symptom scores on 3 validated interstitial cystitis/bladder pain syndrome questionnaires as well as with urinary frequency. However, it was not associated with depression or other common systemic pain problems. These results suggest that low bladder capacity is a marker for a bladder centric manifestation of interstitial cystitis/bladder pain syndrome.

Cryptococcal phospholipase B1 is required for intracellular proliferation and control of titan cell morphology during macrophage infection.

Cryptococcus neoformans is an opportunistic fungal pathogen and a leading cause of fungal-infection-related fatalities, especially in immunocompromised hosts. Several virulence factors are known to play a major role in the pathogenesis of cryptococcal infections, including the enzyme phospholipase B1 (Plb1). Compared to other well-studied Cryptococcus neoformans virulence factors such as the polysaccharide capsule and melanin production, very little is known about the contribution of Plb1 to cryptococcal virulence. Phospholipase B1 is a phospholipid-modifying enzyme that has been implicated in multiple stages of cryptococcal pathogenesis, including initiation and persistence of pulmonary infection and dissemination to the central nervous system, but the underlying reason for these phenotypes remains unknown. Here we demonstrate that a Δplb1 knockout strain of C. neoformans has a profound defect in intracellular growth within host macrophages. This defect is due to a combination of a 50% decrease in proliferation and a 2-fold increase in cryptococcal killing within the phagosome. In addition, we show for the first time that the Δplb1 strain undergoes a morphological change during in vitro and in vivo intracellular infection, resulting in a subpopulation of very large titan cells, which may arise as a result of the attenuated mutant's inability to cope within the macrophage.

Correlation of gene expression with bladder capacity in interstitial cystitis/bladder pain syndrome.

PURPOSE: Interstitial cystitis and bladder pain syndrome are terms used to describe a heterogeneous chronic pelvic and bladder pain disorder. Despite its significant prevalence, our understanding of disease etiology is poor. We molecularly characterized interstitial cystitis/bladder pain syndrome and determined whether there are clinical factors that correlate with gene expression. MATERIALS AND METHODS: Bladder biopsies from female subjects with interstitial cystitis/bladder pain syndrome and female controls without signs of the disease were collected and divided into those with normal and low anesthetized bladder capacity, respectively. Samples then underwent RNA extraction and microarray assay. Data generated by these assays were analyzed using Omics Explorer (Qlucore, Lund, Sweden), GeneSifter® Analysis Edition 4.0 and Ingenuity® Pathway Analysis to determine similarity among samples within and between groups, and measure differentially expressed transcripts unique to each phenotype. RESULTS: A total of 16 subjects were included in study. Principal component analysis and unsupervised hierarchical clustering showed clear separation between gene expression in tissues from subjects with low compared to normal bladder capacity. Gene expression in tissue from patients with interstitial cystitis/bladder pain syndrome who had normal bladder capacity did not significantly differ from that in controls without interstitial cystitis/bladder pain syndrome. Pairwise analysis revealed that pathways related to inflammatory and immune response were most involved. CONCLUSIONS: Microarray analysis provides insight into the potential pathological condition underlying interstitial cystitis/bladder pain syndrome. This pilot study shows that patients with this disorder who have low compared to normal bladder capacity have significantly different molecular characteristics, which may reflect a difference in disease pathophysiology.

Current recommendations for bladder instillation therapy in the treatment of interstitial cystitis/bladder pain syndrome.

Bladder instillation therapy refers to the direct introduction of medication into the bladder and is a common treatment modality for patients with interstitial cystitis/bladder pain syndrome (IC/BPS) who have failed conservative and oral therapies. The current American Urological Association (AUA) recommendations list three medications as options for IC/BPS instillation therapy: dimethyl sulfoxide, heparin, and lidocaine. The purpose of this review is to examine the evidence behind the recommendations for these medications. We also examine several historical or experimental therapies that do not hold recommendations but are still used on rare occasion. Finally, we discuss our bladder instillation strategies as well as potential future research and development in intravesicular therapy.

Pulsed Electromagnetic Field Therapy for Pain Management in Interstitial Cystitis/Bladder Pain Syndrome: A Proof-of-Concept Case Series.

OBJECTIVE: To evaluate the efficacy of pulsed electromagnetic field (PEMF) therapy for symptom and pain management in women with non-bladder centric interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: Women with non-bladder centric IC/BPS and a numeric rating scale score for pelvic pain ≥6 underwent twice-daily 8-minute full body PEMF therapy sessions for 4 weeks. The primary outcome metric was a reduction in pelvic pain score ≥2 points. A 7-day voiding diary (collected at baseline and conclusion), 3 validated symptom scores, and the Short Form-36 Quality of Life questionnaire (completed at baseline, conclusion of treatment, and 8-week follow-up), were used to assess secondary outcomes. Treatment effects were analyzed via Wilcoxon-signed rank test; P < .05 was considered significant. RESULTS: The 4-week treatment protocol was completed by 8 of 10 enrolled patients, and 7:8 (87.5%) had a significant reduction in pelvic pain (-3.0 points, P = .011) after 4 weeks. There was also a significant decrease in scores on all validated IC/BPS questionnaires, daily number of voids, and nocturia symptom score (P < .05). Significant increases in several quality-of-life questionnaire sub-scores were also identified at 4 weeks (P < .05). At 8-week post-therapy, the positive effects were somewhat attenuated, yet 4:8 patients (50%) continued to have significant pain reduction (P = .047). No adverse events or side effects were reported. CONCLUSION: Whole body pulsed electromagnetic field therapy is an alternative treatment option for women with chronic bladder pain syndrome that warrants investigation through comparative trials.

Small-Fiber Polyneuropathy Is Prevalent in Patients With Interstitial Cystitis/Bladder Pain Syndrome.

IMPORTANCE: The pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is imperfectly understood. Recent studies reported that small-fiber polyneuropathy (SFPN) is common in fibromyalgia, a condition commonly comorbid with IC/BPS. OBJECTIVE: The objective of this study was to determine the prevalence of SFPN in a large cohort of IC/BPS patients. METHODS: Adults diagnosed with IC/BPS scheduled to undergo either therapeutic hydrodistention (n = 97) or cystectomy with urinary diversion (n = 3) were prospectively recruited to this study. A skin biopsy obtained from the lower leg was used for intraepidermal nerve fiber density measurement. Small-fiber polyneuropathy (+/-) status was determined by comparing linear intraepidermal nerve fiber density (fibers/mm2) with normative reference values. Demographic information, medical history, and diagnoses for 14 conditions (both urologic and nonurologic) known to co-occur with IC/BPS were documented from self-report and electronic medical record. RESULTS: In this large cohort of patients with IC/BPS, 31% (31/100) were positive for SFPN. Intraepidermal nerve fiber density was below the median for age and sex in 81% (81/100) of patients. Approximately one-third (31%) of SFPN+ patients reported co-occurring chronic fatigue syndrome, compared with 10.6% of the SFPN- group (P = 0.034). Small-fiber polyneuropathy-positive patients reported significantly fewer allergies than SFPN- patients (37.9% vs 60.6%; P = 0.047). There were no significant differences in bladder capacity or Hunner lesion status between the SFPN+ and SFPN- subgroups. CONCLUSIONS: Small-fiber polyneuropathy is a common finding in patients with IC/BPS, and SFPN status is significantly correlated with co-occurring chronic fatigue syndrome and negatively correlated with the presence of allergies in this population.