Interstitial cystitis

Interstitial cystitis (IC) is a disease characterized by frequent, urgent urination and intense pain in the bladder, which significantly affects the quality of life of patients.

Interstitial cystitis is the most common cause of chronic pelvic pain in women and men. 

Patients suffering from interstitial cystitis usually complain of a significant decrease in quality of life and limitations in daily activities. Without timely and correct treatment, IC can lead to bladder atrophy with a sharp decrease in capacity and the formation of microcysts. Unfortunately, in advanced situations, sometimes only surgical removal of the bladder is the only way to restore quality of life
Symptoms Interstitial cystitis creates both psychological and hygienic problems.  Intense and almost constant pain, frequent urination, accompanied by imperative urges, pain and discomfort during sexual activity and sleep disturbance naturally lead to depression, anxiety and isolation. Before the patient learns about his true diagnosis and begins to receive adequate therapy, he goes through a long journey, several years long, which consists of weekly or monthly fruitless visits to doctors in clinics and private medical institutions. As a rule, these patients undergo a large number of unsuccessful courses of therapy with uroseptics, and subsequently with antibacterial drugs, which are prescribed despite normal urinalysis and urine culture. Compounding the situation is the widespread belief in the need for outpatient treatment using harsh chemicals such as silver nitrate instilled into the bladder.
The incidence of this pathology varies from 10 cases per 100,000 population in Finland to 510 cases per 100,000 in the USA (Jones CA, J Urol, 1994). C.L. Parsons et al (2002) reported evidence of IC in 85% of gynecological patients with chronic pelvic pain and rightly consider this bladder disease to be a widespread and underestimated problem. The incidence in women is 10 times higher than in men.
The main clinical manifestation in patients is pain. The intensity of pain with interstitial cystitis ranges from mild burning and discomfort to severe, unbearable pain in the bladder, lower abdomen, perineum, pelvis, vagina, sacrum and thighs. In a typical course, pain increases as the bladder fills, reaching its peak at the height of the urge to urinate and during the first minutes after it. Patients usually note periods of exacerbation of the disease and remission, which are not seasonal and individual for each patient. The most frequently recorded dependence of the intensity of pain in women is on menstrual flow, in particular during the premenopausal period.
The progression of the disease Interstitial cystitis, as a rule, leads to a marked decrease in the effective volume of the bladder and the formation of the so-called microcyst, when the bladder capacity does not exceed 80-100 ml, while most patients tend to empty the bladder at a significantly lower filling.
Etiology
The etiology of IC (Interstitial cystitis) is unknown. This explains a large number of hypotheses, which, however, are not sufficiently confirmed by facts.
Infection. So far, it has not been possible to detect any microorganism that could be the cause of IC. However, the possibility that some microorganism contributes to the development of IC is still an open topic.
Inflammation is an important part of the clinical picture of classic IC. Histological examination of biopsies of the bladder wall revealed pancystitis and perineural inflammatory infiltrates of lymphocytes and plasma cells. In the case of non-ulcerative interstitial cystitis, inflammatory changes are minor.
Mast cell activation. Mast cells are multifunctional immune cells containing very powerful inflammatory mediators such as histamine, leukotrienes, serotonin and cytokines. Many of the symptoms and histological findings in classical IC, such as pain, urinary frequency, edema, fibrosis and neovascularization in the lamina propria, may be caused by the release of these biologically active substances by mast cells. The number of mastocytes in the bladder tissue of patients with classic IC exceeds this indicator in the group of control patients by 10 times.
Urothelial dysfunction/pathology of the glycosaminoglycan layer. All patients with IC experience some type of failure of the bladder mucosa, which manifests itself in the appearance of tears and cracks when the bladder is stretched (“cracking” of the mucosa). Electron microscopy reveals expansion of intercellular spaces and increased permeability of the bladder mucosa. These changes are correlated with disruptions in the glycosaminoglycan layer. This hypothesis was proposed by Parsons and Mulholland (J Urol., 1987 and 1991). They indicate that due to damage in the glycosaminoglycan layer, the nerve endings of the mucous membrane are exposed to aggressive chemical products of urine.
Autoimmune mechanisms. A large number of immunological studies have been conducted in patients suffering from IC, but the results of these studies are far from concrete and contradictory. Immunohistochemical and cytofluorometric analyzes of the bladder mucosa demonstrated differences between patients with classic and non-ulcer IC. In cases of classical IC disease, T cell infiltrates and B cell nodules were observed, whereas in nonulcer IC only some T cell infiltration was observed (Harrington DS et al., J Urol., 1990). Poor characterization of patients in many studies, especially when defining subtypes of patients with IC, often prevents the use of the data obtained.
Other etiological factors for IC include impaired nitric oxide metabolism, increased sympathetic innervation and activation of purinergic transmission, bladder hypoxia, but further research is needed to confirm them.
Diagnostics
At present, diagnostic standards for IC remain an unresolved problem. Due to the incomplete and ambiguous understanding of the etiology and pathogenesis of this disease and the lack of a characteristic clinical picture, diagnosis is based on the exclusion of conditions that may mask IC or are incompatible with IC.  The currently generally accepted exclusion criteria for IC are those adopted by the Interstitial Cystitis Association (ICA) and the National Institutes of Health (NIH/NIDDK):
  • Bladder capacity greater than 300 ml by gas or liquid cystometry.
  • Absence of intense urgency to urinate when filling the bladder with 100 ml of gas or 150 ml of liquid at a rate of 30 to 100 ml/min during cystometry.
  • Presence of involuntary detrusor contractions during filling cystometry.
  • Duration of symptoms less than 9 months
  • Absence of nocturia.
  • Clinical improvement when taking uroantiseptics, antimicrobials, anticholinergics or antispasmodics.
  • Frequency of urination less than 8 times a day.
  • Diagnosis of bacterial cystitis in the previous 3 months.
  • Stones of the distal ureter and bladder.
  • Active genital herpes.
  • Cancer of the urethra and female genital organs.
  • Urethra diverticula.
  • Cyclophosphamide and other types of chemical cystitis.
  • Tuberculous cystitis.
  • Post-radiation cystitis.
  • Benign and malignant tumors of the bladder.
  • Vaginitis.
  • Under 18 years of age.
  • Before performing diagnostic procedures and laboratory tests, it is necessary to collect a detailed medical history, taking into account the time of onset of the disease, its course and the effectiveness of previous treatment measures, etc.
A mandatory component of the examination is a questionnaire, which is used to subjectively assess the condition of your bladder, the severity of pain and the degree of impact of the disease on the quality of life (Problem index, O’Leary-Sant Questionnaire, 1997; Universaty of Wisconsin Interstitial Cystitis Scale, 1998). A urination diary is filled out in which the patient notes the effective volume and time of each urination for 3 days.
The first stage of the study is microscopy of the urine sediment and culture, which allows us to exclude a urinary tract infection. An objective examination should include a gynecological examination in women and a digital rectal examination in men in order to exclude inflammatory diseases of the genital organs, urethral diverticula and the presence of neoplasms.   
Ultrasound of the genitourinary organs is also performed to exclude oncological processes.  It is mandatory to exclude tuberculous lesions of the bladder and other specific diseases, such as herpes infection, radiation injuries and chemical cystitis.
The second stage of diagnosis includes a potassium test (Parsons test). This test can be performed on an outpatient basis, does not require much time, and is minimally invasive.  When performing the test, 40 ml of water for injection and potassium solution (KCL) – 40 mEq/L are alternately injected into the bladder. The patient alternately, for each solution, determines the severity of pain and urge. The test is based on the theory of disruption of the integrity of the bladder mucosa, in particular the glycosaminoglycan layer, and the penetration of an aggressive urinary environment (and in this case, potassium) into the thickness of the bladder wall, which causes irritation of the nerve endings.  Parsons performed a potassium test on 1,500 patients with IC, and 80% tested positive. In the healthy control group, a positive potassium test was observed in 4% (Parsons C.L. et al 2002). According to Chambers G.K. et al (1999), the sensitivity of the potassium test is 69.5%, specificity 59%. Given these characteristics, the test is not included in the NIH/NIDDK exclusion criteria and cannot be recommended as the only diagnostic test. The test results should be considered in conjunction with the clinical picture and cystoscopic data.
Urodynamic testing according to recent consensus is not mandatory for the diagnosis of IC, but may provide useful information for the differential diagnosis. Typically, cystometry in patients with IC shows sensory urgency and instability, decreased bladder capacity, and pain when the bladder is low.
Cystoscopy is one of the main diagnostic methods for IC. Cystoscopy is performed under epidural anesthesia. G.L. Hunner first described, in 1914, a “simple” bladder ulcer associated with severe inflammation and decreased bladder capacity in patients with urgent symptoms and intense pain.  This symptom complex is characteristic of interstitial cystitis.  However, much more often, up to 90%, ulcerative changes are not detected.  Accordingly, depending on the cystoscopic picture, two forms of IC are distinguished: “classic” IC with the presence of a Hunner’s ulcer and non-ulcerative “early” cystitis.  Cystoscopy is combined with hydrodistension of the bladder (P.Walsh, 1978) and subsequent re-examination. The appearance of diffuse foci of petechial, submucosal hemorrhages – glomerulation and ruptures (“cracking”) of the bladder mucosa with “waterfall” type bleeding in more than 2 cystoscopic fields of view, after hydrodistension, are criteria for confirming IC in the absence of Hunner’s ulcer.
Bladder biopsy is the final part of cystoscopy. A multifocal biopsy is performed, taking about 6 tissue samples from the bladder wall. Histological examination allows us to exclude carcinoma in situ and document the presence of inflammation of the bladder wall, its severity and the cellular composition of the infiltrate, in particular mastocytosis.
Currently, work continues to identify IC markers. Key et al. from the University of Maryland reported the identification of antiproliferative factor (APF) in urine, which inhibits the regeneration of epithelial cells of the bladder mucosa.  APF levels in IC patients are significantly higher than in controls, with 94% specificity and 95% sensitivity for IC versus controls (Keay et al, Urology, 2001). Byrne JS et al. (J Urol., 1999) reported a significant decrease in the level of GP-51, an epithelial glycoprotein, in patients with IC versus controls. The most comprehensive review of the literature on IC markers is presented by Erickson et al. in the journal Urology in 2001.
Treatment
Given that IC is an inflammatory disease of unknown etiology, its treatment is mainly aimed at relieving the symptoms that cause suffering to patients.
Various treatment methods are used:
—intravesical instillation of medicinal substances;
—hydraulic stretching of the bladder under anesthesia;
—oral treatment;
—physiotherapy;
—non-drug methods;
—surgical treatment.
Some reports indicate a 90% success rate when multiple treatments are used in combination. According to many clinics, instillations of a 50% solution of dimethyl sulfoxide, cocktails with an antibiotic, hydrocortisone and lidocaine, heparin instillations, as well as instillations of chondroitin sulfate, pentosan or hyaluronic acid are successfully used as intravesical therapy to restore the integrity of the glycosaminoglycan layer.
Hydraulic distension of the bladder is both diagnostic and therapeutic, since after distension, patients suffering from IC report a significant improvement in well-being, which can last for many months and even years.
We should also not forget about the long-used urothelium-destroying agents, which, according to some experts, contribute to the desquamation of defective urothelium and the rapid restoration of normal ones (dimethyl sulfoxide, chloropactin).
Adjunctive oral therapy:
— analgesics / morphine derivatives / cyclooxygenase type 2 inhibitors (COX-2): diclofenac, metamizole, buprenorphine, levomethadone, meloxicam, celecoxib;
— antihistamines and corticosteroids: suprastin, loratadine, prednisolone;
—H2-histamine receptor antagonists: cimetidine, ranitidine, famotidine;
— antidepressants: amitriptyline, doxepin;
—nitric oxide donors: L-arginine;
—muscarinic receptor blockers—oxybutynin, tolteradine, which have a pronounced positive effect both in IC and in symptoms of overactive bladder.
Recently, more and more reports have appeared in the literature about positive results of treatment of IC with botulinum toxin, which is injected under the mucous membrane of the bladder, and the BCG vaccine, administered intravesically.
Antibiotics for IC are rarely used, and generally not so much as the main treatment, but to prevent the addition of a urinary infection.
According to the literature, in the subacute period of IC, endovesical iontophoresis, laser photoirradiation of the bladder, UHF, inductotherapy, and balneotherapy have a positive effect.
It can therefore be concluded that Interstitial cystitis appears to be a multifactorial disease, possibly occurring in people with a genetic predisposition. Despite the long period of study of this disease, it remains unclear whether IC is a homogeneous disease or a collection of different bladder diseases. Perhaps Interstitial cystitis is a manifestation of some kind of autoimmune syndrome. And although the significance of the infectious factor in the development of the disease has not been proven, it cannot be ruled out that it is chronic persistent infection that causes such changes, at least in part.
One of the urgent tasks of modern urology is the development of new diagnostic criteria and methods, as well as the systematization of existing criteria for selecting patients with IC. To understand the pathogenesis of this unstudied disease, it is also important to identify new markers of the disease. Treatment regimens for the disease have not been systematized and, unfortunately, at this stage require further research.