Treatment approaches for interstitial cystitis: multimodality therapy

Interstitial cystitis is an increasingly common disease characterized by urgency, frequency, and pelvic pain. Its etiology is poorly understood but is likely to be multifactorial. A proposed pathophysiology describing a cascade of events, including epithelial dysfunction, mast cell activation, and neurogenic inflammation, is presented. Using this model, multimodality therapy regimens have been developed that treat all components of this cascade. Multimodality therapy appears more effective than single agents in the treatment of interstitial cystitis.     

Interstitial cystitis: characterization and management of an enigmatic urologic syndrome

The enigmatic urologic condition known as interstitial cystitis has an estimated prevalence of 0.01% to 0.50% of the female population. Its etiology is unknown but may involve microbiologic, immunologic, mucosal, neurogenic, and/or other, as yet undefined, agents. There is no gold standard for the diagnosis of interstitial cystitis; rather, it is a diagnosis of exclusion. It is impossible to provide a purely evidence-based treatment strategy, but review of available evidence suggests that conservative supportive therapy (including diet modification); oral treatment with pentosan polysulfate, amitriptyline, hydroxyzine, or cimetidine; and intravesical treatments with heparinoids, dimethyl sulfoxide, alkalized lidocaine, or bacille Calmette-Guérin may be effective in some patients.     

Mast cell-derived histamine mediates cystitis pain

Background

Mast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC.

Methods and Findings

Infection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology.

Conclusions

These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, and histamine receptors represent direct therapeutic targets for pain in IC and other chronic pain conditions.     

Calcifying nanoparticles associated encrusted urinary bladder cystitis

Encrusted cystitis is a subtype of chronic cystitis characterized by multiple calcifications in the form of plaques located in the interstitium of the urinary bladder mucosa and frequently associated with mucosal ulcers. It is a very rare disease of controversial etiology. Our transmission electron microscopy of the calcified plaques of encrusted cystitis has revealed that the smallest formed particles (elementary units) of these calcifications are electron-dense shells surrounding an electron lucent core, diagnostic of calcifying nanoparticles (previously called nanobacteria). We pioneer the notion that calcifying nanoparticles are the causative agents of encrusted urinary bladder cystitis.     

Economics of interstitial cystitis in clinical practice

Urologists may be concerned that treatment of patients with interstitial cystitis (IC) is not economically feasible, and the time spent on these patients could be used for more profitable urologic therapy. However, care of IC patients can provide urologic practices with increased revenue opportunities through a wide range of procedures, including IC evaluation and management, treatment planning, and diagnostic, therapeutic, and even surgical techniques. Current Procedural Terminology (CPT) and evaluation and management (E&M) charge codes are provided for many types, levels, and complexities of IC procedures. Some of these treatments may use physician extenders who generate profits without additional overhead costs. Further, IC therapy may involve the use of many in-office services, such as urodynamics, biofeedback, and peripheral nerve stimulation that can be economically profitable. Rather than being an economic drain, patients with IC can enhance the profitability of a urologic practice while they receive much needed care.     

Neuromodulation for the treatment of refractory interstitial cystitis

Interstitial cystitis (IC) is a symptom complex of urinary urgency, frequency and pelvic pain. Multimodality behavioral and phamacologic treatment is often effective in treating IC. Unfortunately, some patients with IC are refractory to standard treatments. Neuromodulation has been shown to be effective in treating voiding dysfunction. Small studies have demonstrated improvement in pelvic pain and IC symptoms during temporary sacral nerve stimulation. This current study demonstrates that patients refractory to traditional therapies for IC can respond well to sacral nerve stimulation and maintain improvement in symptoms after permanent implantation of a neurogenerator. The technique used to place the neurostimulator can impact on the degree of the response and the complication rate. Sacral neurostimulation continues to evolve and should be in the armamentarium available to treat voiding dysfunction.     

Cell signaling in interstitial cystitis/painful bladder syndrome

Evidence for several types of cell signaling abnormalities has been presented for patients with interstitial cystitis/painful bladder syndrome (IC/PBS), a poorly understood chronic painful bladder disorder for which currently there is no reliable effective therapy. Increases or decreases in various urine cytokines and growth factors have been found in patient specimens, along with abnormal expression of epithelial differentiation markers, growth factors, cell membrane proteins, neurotransmitters, and other cytokines in tissue biopsies and/or explanted bladder cells from IC/PBS patients. Some of the abnormalities found in bladder epithelial cells from IC/PBS patients have been shown to be induced in normal cells by an antiproliferative factor from IC/PBS bladder epithelial cells that binds to a functional cell membrane receptor (CKAP4/p63). Greater understanding of cell signaling events associated with this debilitating disorder may lead to the development of more effective therapies.     

A model for experimental bacterial cystitis in the dog

To induce an experimental model of bacterial cystitis, ten preconditioned dogs underwent bladder irritation with a 0.1% alcoholic solution of salicylic acid followed in 24 hours by an intravesicular infusion of Proteus mirabilis. The dogs were observed for the following 14 days (five dogs) and 17 days (five dogs) and then euthanatized and necropsied. Tenesmus, dysuria, hematuria, and pollakiuria occurred in all dogs, but the severity of these signs diminished with time. The total white cell, neutrophil, and monocyte counts in the peripheral blood increased and urinalysis results were consistent with infection and severe inflammation. The infection persisted for the duration of the study, although the average quantitative bacterial count in urine progressively declined. No changes occurred in the measured clinical chemistry values. Severe inflammation was present on gross examination of the bladder and microscopic examination of the bladder, prostate, and renal pelvis. Less severe inflammation was present on microscopic examination of the urethra and ureter.