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Ashok Batra, MD, State University of New York Health Science Center, Syracuse. Infect Urol 12(6):155-158, 1999 Abstract Interstitial cystitis (IC) is characterized by irritative bladder symptoms and bladder or perineal pain with negative urine culture and cytology. IC may be a composite of various etiologic insults to the bladder. Although the etiology and pathogenesis of the transmural inflammation in IC have been an area of intense research, they are still unclear. The diagnosis is one of exclusion, and the treatment is usually empiric. Treatment should be individualized. Introduction Interstitial cystitis (IC) is characterized by a constellation of symptoms that include bladder/pelvic pain associated with urgency, frequency, and dysuria. One study estimated that approximately 500,000 individuals in the United States have IC, the vast majority of whom are adult women; only 10% are men.[1] Etiology Infection Many IC patients have a history of recurrent urinary tract infection (UTI).[2] Some theorize that the causative bacteria in IC may be fastidious or present in small numbers.[3,4] The presence of an infectious agent may not produce IC, but it may be responsible for an inflammatory or an immunologic response.[4] Molecular biologic techniques, such as polymerase chain reaction, have been used to amplify bacterial genes in an attempt to identify any bacteria present either in the tissue or the urine.[5] Tissue biopsy specimens from the bladder and urine samples studied for the presence of various fastidious organisms, including Mycoplasma, Ureaplasma, Mycobacterium, Campylobacter, Helicobacter, Hemophilus, and viruses, have identified no causative infectious agent for IC.[6] Leaky Urothelium This concept theorizes that a leaking urothelium has a deficient glycosaminoglycan (GAG) surface.[7,8] A leaky urothelium allows the urine to enter the interstices of the bladder wall, resulting in a diffuse transmural inflammation responsible for the symptoms of IC. It is unclear whether the GAG layer is dysfunctional, deficient, or absent in patients with IC.[8] The leak can be due to a congenital structural or functional deficiency of the mucosa or acquired due to a toxin in the urine.[9] However, ultrastructural, biochemical, and functional studies fail to support this increased permeability theory.[10,11] Immunologic Patients with IC often have associated chronic immunologic disorders, such as systemic lupus erythematosus, scleroderma, fibromyalgia, and Sjögren's syndrome.[12,13] These patients may have antibodies against mucosal or muscle cells and/or various other connective tissue components of the bladder.[12,14,15] One study showed that nitric oxide, which is involved in various immune and inflammatory mechanisms, is elevated 16-fold in patients with IC as compared with controls.[16] Although it is assumed that some immune mechanisms are involved in IC, no definitive causal link has been established. Neurogenic Inflammation Neurogenic inflammation has also been proposed in the etiology of IC.[17] Mast cells are triggered by various mechanisms and are responsible for releasing vasoactive substances that cause inflammation.[18] Studies have demonstrated the presence of mast cells near the sensory nerve terminals of the bladder.[18] Once these mast cells are activated, neurogenic inflammation occurs either acutely or as a subacute reaction. The fact that most patients with IC are women suggests that the process involving mast cells may be hormonally influenced by estrogens.[19] Neurogenic inflammation may explain symptoms in patients with normal-looking bladders with good capacity. Pathology There are no pathognomic histologic findings in this disease. Various features of chronic inflammation have been described. Elbadawil[17] performed an ultrastructural study of nonulcerative IC patients and noted the following: a) discohesive uroepithelium with a disrupted and permeable barrier; b) accelerated uroepithelium turnover rate; c) querciphylloid profiles of detrusor muscle cells; and d) damage of intrinsic nerve and blood vessel walls. There was also fluid engorgement of the tissues with cellular infiltrate primarily composed of lymphocytes and activated mast cells, supporting a neurogenic etiology of IC. Future ultrastructural analysis confirming these new histologic findings may lead to the ability to make a primary diagnosis of IC, rather than one of exclusion. Diagnosis Hunner first described the ulcerative form of IC in 1915.[20] Since then, there has been no agreed upon criteria for the diagnosis of IC. In 1987, the National Institutes of Health (NIH) convened a workshop that developed diagnostic criteria for a research definition of IC (Table I).[21] Current standard of practice requires urine cultures, cytologies, urodynamic study, cystoscopy, and biopsy to essentially rule out other diseases. More recently, attempts have been made to diagnose IC by measuring various biochemical markers in urine and bladder biopsy specimens, such as nitric oxide synthase and heme oxygenase,[22] Tamm-Horsfall protein,[23] GAG, and hyaluronic acid.[24] Urinary measurements of heparin binding epidermal growth factor (HB-EGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) have also been done.[25] Keay and others[25] reported the concentration of HB-EGF was strikingly lower in patients with IC, whereas EGF, IGF-1, and IGFBP-3 urinary levels were significantly elevated in patients with IC when compared with controls. One study proposed diagnosing IC based on the alteration of mast cells and nerve fibers in the bladder of patients with IC using quantitative image analysis and morphometry (QIAM).[26] Hofmeister and colleagues[26] proposed that if the detrusor to mucosa mast cell ratio (DM:MCR) is >0.75, then IC is present. If DM:MCR is <0.5, then IC is not present. With DM:MCR between 0.5 and 0.75, a quantitative S-100 protein staining analysis could be employed to evaluate nerve fiber proliferation to help elucidate IC in these marginal cases. There is no standard test to establish the diagnosis of IC, but it is hoped further research will lead to a unified system of diagnosis of this complex disease. Currently, patients are routinely treated who do not fulfill the NIH research criteria (Table I). Those who fulfill the exclusion and inclusion criteria indeed have IC. However, if a patient does not fulfill either criteria, he or she may still have IC. Treatment. IC is physically debilitating as well as emotionally distressing for many patients who suffer from it. An understanding and sympathetic attitude is important in treating these patients. Patient education remains the cornerstone of successful therapy. Surgical intervention should be used only as a last resort. Treatment is individualized with the goal of symptomatic relief. The 10 most commonly used specific therapies currently are: hydrodistention, amitryptyline, special diet (avoidance of caffeine, alcohol, and acidic beverages), intravesical heparin, hyoscyamine, oxybutynin, pentosan polysulfate, propoxyphene, a methenamine combination, and hydroxyzine.[27] Table II summarizes widely used therapies. Oral Preparations Amytriptyline,[28] a tricyclic antidepressant, has become a staple of oral treatment for IC with a success rate of 64% to 90% at 2 to 14 months of follow-up. A dosage of 25 mg at bedtime that is gradually increased to 75 mg over a 2-week period is recommended. The antihistamine hydroxyzine[29] is administered in a 25 mg dosage before bed. This is increased to 50 mg at night and 25 mg in the morning over a 2-week period if sedation is not a problem. Symptomatic improvement is experienced by 30% of patients.[29] The use of sodium pentosan polysulfate is based on the hypothesis that it replenishes the deficient GAG layer, thereby protecting it from further injury from toxic agents.[30,31] A dose of 100 mg, 3 times a day, is recommended. Although early studies showed some promise in selected patients,[30] a more recent study did not support the initial enthusiasm for this agent.[32] Antibiotics such as ciprofloxacin, rifampin, and metronidazole have been used with varying degrees of success. These agents are not recommended for long-term use because of potential adverse effects. L-arginine was successfully used to treat IC by some investigators,[33] while others did not find it as effective.[34] A pilot study from northern Ireland utilized a prostaglandin analogue, misoprostol, which has shown some promise.[35] Nifedipine,[36] nalmefene,[37] and cyclosporine[38] have also been used with limited success. Intravesical Agents Intravesical
agents in the form of dimethyl sulfoxide (DMSO), oxychlorosene sodium, heparin,
lidocaine, bicarbonate, and Our initial intravesical therapy includes instillation of a mixture of 50 mL of 50% DMSO, 10,000 U of heparin, 10 mg triamcinolone, and 44 mEq bicarbonate administered weekly for 6 weeks.[39] Alternative intravesical therapy is oxychlorosene sodium,[42] using 0.4% solution administered at 10 cm H20 under anesthesia. Multiple instillations can be given, with a 1 month pause after the first 2 to wait for a therapeutic response. Reported success rate was 72% with an average 6 month duration of response.[42] Other Therapies Behavioral modification techniques using electrical stimulation have achieved some success in suppressing bladder overactivity. Sacral nerve implantation techniques are undergoing trials for the treatment of bladder frequency, urgency, and pain.[43] Transcutaneous electrical nerve stimulation (TENS) has been attempted to alleviate pain and frequency.[44] Similarly, acupuncture and pain blocks have been moderately successful. Some patients require opioid analgesics to alleviate chronic pain. Surgical Therapy Surgical therapy for IC should be used as a last resort after all trials of conservative treatment have failed. The procedure of choice is supravesical urinary diversion with or without cystectomy. Conclusion. Despite extensive research over the last decade, the etiology and pathogenesis of this very perplexing disease remain unclear. This entity remains enigmatic, perhaps because it is a disease with multiple etiologies. After recurrent insults, the bladder in a patient with IC responds with local pain and irritative symptoms. Therapy must be individualized according to each patient's needs.
Table I. NIADDK Research Definition of Interstitial Cystitis Inclusion criteria: Glomerulations or Hunner's ulcer on cystoscopic examination, and Pain associated with the bladder or urinary urgency Exclusion criteria: 1. Bladder capacity >350 mL on awake cystometry using either gas or liquid as filling medium. 2. Absence of intense urge to void with bladder filled to 100 mL of gas or 150 mL of water during cystometry, using a fill rate of 3-100 mL/mm 3. Demonstration of phasic involuntary bladder contractions during cystometry using fill rate described above 4. Duration of symptoms less than 9 months 5. Absence of nocturia 6. Symptoms relieved by antimicrobials, urinary antiseptics, anticholinergics, or antispasmodics (muscle relaxants) 7. Frequency of urination while awake <8 times per day 8.
Diagnosis of bacterial cystitis or prostatitis within 3 month period 9.
Bladder or lower ureteral calculi 11.
Uterine, cervical, vaginal, or urethral cancer 12.
Urethral diverticulum 13.
Cyclophosphamide or any type of chemical cystitis 14.
Tuberculous cystitis 15.
Radiation cystitis 16.
Benign or malignant bladder tumors 17.
Vaginitis 18.
Age <18 years Therapy
Comments/Response Amitriptyline
- Antidepressant; peripheral anticholinergic action;
64%-90% response in various series Hydroxyzine
- H1 antagonist; up to 30% response Pentosanpolysulfate
- Restores epithelial permeability barrier; contradictory results Nalmefene
- Opioid antagonist; up to 59% response; investigational Nifedipine
- Calcium channel blocker; up to 75% response; investigational DMSO
- Lignin derivative; sometimes usedwith other agents; up to 90%
response rate Oxychlorosenesodium
- Bleach-like intravesical agent;
anesthesia required; up to 72% response TENS
- Variable results; up to 28%
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