AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Interstitial cystitis (IC) is a clinical syndrome characterized by daytime and nighttime urinary frequency, urgency, and pelvic pain of unknown etiology. IC has an unclear etiology and pathophysiology and undefined diagnostic criteria. Despite considerable research, universally effective treatments do not exist, and therapy usually consists of various supportive, behavioral, and pharmacological measures. Surgical intervention is very rarely indicated.

History of the Procedure

In 1887, Skene initially described a condition characterized by inflammation that destroyed the urinary bladder "mucous membrane partly or wholly and extended to the muscular parietes." Guy Hunner popularized the disease with the description of characteristic bladder wall ulcers. The first comprehensive epidemiological description of IC is credited to Hand (1949), who described the widespread, small, submucosal bladder hemorrhages and the significant variation in bladder capacity.

Problem

Despite years of intensive research, no specific clinical or urinary markers; radiographic, laboratory, or serologic findings; or biopsy patterns exist that are pathognomonic for IC. IC is a diagnosis of exclusion. One obstacle in the diagnosis and management of IC is the lack of a consensus clinical definition. No universally accepted clinical criteria exist for the diagnosis of IC.

The differential diagnosis of urinary frequency, urgency, and/or pain includes the following:

• Infectious or inflammatory conditions such as recurrent urinary tract infection (UTI), urethral diverticulum, infected Bartholin gland or Skene gland, vulvovestibulitis, tuberculous/eosinophilic cystitis, vaginitis (eg, bacterial, viral [eg, herpes]), or schistosomiasis
• Gynecologic causes such as pelvic malignancy or mass (eg, fibroid, endometrioma), endometriosis, mittelschmerz, pelvic inflammatory disease, or genital atrophy
• Urologic causes such as bladder cancer or carcinoma in situ (CIS), radiation cystitis, overflow incontinence, acontractile detrusor, prostatodynia, chronic pelvic pain syndrome, bladder outlet obstruction (eg, urinary retention with overflow incontinence), large postvoid residual volume, or open bladder neck (eg, intrinsic sphincteric deficiency, urolithiasis, urethritis)
• Neurologic causes such as detrusor hyperreflexia, Parkinson disease, lumbosacral disk disease, spinal stenosis, spinal tumor, multiple sclerosis, or cerebrovascular accident
• Other possible diagnoses, including dysfunctional voiding, vulvodynia, pelvic floor myalgia, degenerative joint disease, hernia, inflammatory bowel disease, gastrointestinal neoplasm, diverticulitis, or adhesions from prior surgery

Clinically, the practitioner is somewhat obligated to consider these potential alternative diagnoses prior to conferring the diagnosis of IC on a patient. The implications of a diagnosis of IC are profound in that it is a chronic condition without universally effective therapy.

Frequency

• Prevalence: Reports on the prevalence of IC conflict depending on the country of origin and the criteria used for diagnosis. In the United States, Curhan et al showed a prevalence of 60-70 cases per 100,000 women, whereas reports from Europe indicate a prevalence of 18 cases per 100,000 women and only 3-4 cases per 100,000 women in Japan. These marked differences are likely due to differences in diagnostic criteria, varying from all-encompassing clinical criteria (eg, those from the National Institute of Diabetes & Digestive & Kidney Diseases [NIDDK] of the US National Institutes of Health) to very strict criteria based on a pathologic diagnosis. The incidence rate of IC is 2.6 cases per 100,000 women per year in the United States.
• Race: Of patients with IC, 94% are white. IC appears to be slightly more common in Jewish women.
• Sex: Approximately 90% of patients with IC are female. Household size, marital status, number of male sexual partners, educational status, and parity are not statistically different between patients with IC and healthy controls.
• Age: Median age at presentation is 40 years. However, Close et al from Seattle have shown that IC may occur in children. In their series, the median age of onset was 4.5 years, with a mean age of diagnosis of 8.2 years. The children had diffuse glomerulations and terminal hematuria. Of the 16 children in the study, 15 improved after bladder hydrodistention.
• Family history: Although traditionally IC has not been considered a hereditable condition, a recent study from the University of Maryland reports a higher occurrence of IC in monozygotic versus dizygotic twins, suggesting the disease has at least a partial genetic predisposition.
• Associated medical conditions: Patients with IC are more likely to have prior gynecologic surgery and/or a history of UTIs and are 10-12 times more likely to report childhood bladder problems. Associations exist with chronic illnesses, including inflammatory bowel disease, systemic lupus erythematosus, irritable bowel syndrome, fibromyalgia, and atopic allergy.

Etiology

The etiology of IC remains unknown and is likely multifactorial. Proposed etiologies include the following:

• Pathogenic role of mast cells in the detrusor and/or mucosal layers of the bladder
• Deficiency in the glycosaminoglycan layer on the luminal surface of the bladder, resulting in increased permeability of the underlying submucosal tissues to toxic substances in the urine
• Infection with a poorly characterized agent (eg, a slow-growing virus or extremely fastidious bacterium)
• Production of a toxic substance in the urine
• Neurogenic hypersensitivity or inflammation mediated locally at the bladder or spinal cord level
• Manifestation of pelvic floor muscle dysfunction or dysfunctional voiding
• Autoimmune disorder

Pathophysiology

The pathophysiology of IC is poorly understood. Various etiologies have been proposed, none of which adequately explains the variable presentations, clinical courses, or responses to therapies. This may indicate that IC represents a number of as yet undefined disparate pathological conditions that, over time, ultimately present as the clinical syndrome of urinary frequency, urgency, and pelvic pain.

Clinically, IC is often divided into 2 distinct subgroups based on intraoperative findings at cystoscopy and bladder overdistension. These categories are the ulcerative (ie, classic) and nonulcerative (ie, Messing-Stamey) types.

A diffusely reddened appearance to the bladder surface epithelium associated with one or more ulcerative patches surrounded by mucosal congestion (ie, Hunner ulcer) on the dome or lateral walls of the bladder upon cystoscopic examination is the hallmark of classic IC. These ulcers may become apparent only after overdistension because discreet areas of mucosal scarring rupture during the procedure. Overdistension in this type of IC results in fissures and cracks that bleed in the bladder epithelium. In the United States, this type occurs rarely (<10% of cases), and some authors consider this type to be more resistant to therapy. Biopsy findings show that the ulcerative lesion can be transmural, associated with marked inflammatory changes, granulation tissue, mast cell infiltration, and, in some cases, fibrosis. This classic form of IC can be associated with progressively smaller bladder capacity over time.

The nonulcerative type of IC is characterized by similar clinical symptoms (ie, frequency, urgency, pelvic pain), but the cystoscopic findings noted above are absent. However, following overdistension, these patients demonstrate glomerulations that are discreet, tiny, raspberrylike lesions appearing on the dome and lateral walls of the bladder and tiny mucosal tears and submucosal hemorrhages. Bladder biopsy findings in these patients often are unremarkable compared to those found in patients with the classic type.

Clinical

Because IC is a poorly defined entity of unknown etiology, the clinical presentation often is not uniform and the symptoms are variable in severity and nature.

The onset of symptoms is often but not invariably acute, and the patient is sometimes able to describe the moment at which symptoms began. Patients often associate the onset of symptoms with a specific UTI, catheterization, or bladder or pelvic surgery.

Patients with IC have a high incidence of associated conditions including allergies, irritable bowel syndrome, fibromyalgia and focal vulvitis.

IC is characterized by periods of exacerbation followed by variable periods of remission. Symptoms of frequency, urgency, pain, and dysuria may vary daily or weekly or may be constant and unrelenting for months or years and then resolve spontaneously with or without therapy. In females, symptoms may fluctuate relative to the ovulatory cycle. In addition, recent data suggest that some pregnant patients may experience periods of remission during the second and third trimester.

Patients may describe pressure, discomfort or pain in the pelvis, a vague sense of incomplete bladder emptying, or a constant sensation or compulsion to void. Furthermore, a substantial emotional and psychological overlay to the complaints due to the duration and severity of symptoms may or may not be present, and patients may have had an incomplete response to prior therapies.

Spontaneous remission occurs in as many as 50% of patients at a mean of 8 months. Patients may experience complete and spontaneous relief from the symptoms, may undergo a waxing and waning course, may be completely asymptomatic with intermittent flares, or may have a chronically progressive course of increasing symptoms over several years.

The most prevalent feature of IC is irritative lower urinary tract symptoms, including urinary frequency. The exact number of micturitions, daytime or nighttime, is not important; however, according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria, more than 8 micturitions per day is considered adequate for inclusion into clinical studies. Daytime frequency in the absence of nocturia is not characteristic of IC. The absence of significant nocturia may suggest an alternative diagnosis (eg, sensory urgency).

Pain with bladder filling is a common finding that may be reproduced urodynamically or with cystography. Patients may complain of constant pelvic pain or pain related to a full bladder. Dyspareunia is common in as many as 50% of women. Men may report perineal, groin, penile, or scrotal pain; the diagnosis of prostadynia or nonbacterial prostatitis (chronic pelvic pain syndrome) should be entertained. Urinary incontinence is quite rare. Patients with a primary complaint of incontinence may require further evaluation, including urodynamic studies.

Patients with IC have a high incidence of associated conditions, including allergies, irritable bowel syndrome (IBS), fibromyalgia, and focal vulvitis.

The diagnosis of IC is most often made when the long-standing symptoms of urinary frequency, urgency, and pelvic pain exist in the absence of a readily identifiable etiology such as UTI. Urinalysis and urine culture are mandatory. A voiding diary is helpful in establishing baseline voiding frequency. Cystoscopy is considered by some clinicians to be mandatory in order to make the diagnosis of IC; however, this is somewhat controversial due to the lack of specific or pathognomonic findings (except perhaps the very rare finding of a Hunner ulcer). Urodynamic evaluation is optional, and finding detrusor overactivity or pelvic floor dysfunction may suggest an alternative diagnosis.

The International Continence Society prefers the term painful bladder syndrome (suprapubic pain with bladder filling associated with increased daytime and nighttime frequency in the absence of proven urinary infection or other obvious pathology) and reserves the diagnosis of IC for patients with typical cystoscopic and histiologic features. To clarify the criteria for diagnosis, some clinicians prefer the term painful bladder syndrome or interstitial cystitis, defined as a syndrome of chronic pain, pressure, or discomfort associated with the bladder, usually accompanied by urinary frequency in the absence of any identifiable cause.

Because no pathognomonic criteria exist for the diagnosis of IC, the modified NIDDK criteria for the inclusion of patients in IC basic and clinical research studies can be used. These criteria, initially developed in 1987, became the de facto definition of the disease; however, a significant number of patients with IC do not meet these criteria.

National Institute of Diabetes and Digestive and Kidney Diseases criteria

One of the following cystoscopic findings after distension under anesthesia for 1-2 minutes at 80-100 cm water:

• Glomerulations in at least 3 quadrants of the bladder and at least 10 glomerulations per quadrant
• Classic Hunner ulcer

One of the following subjective symptoms:

• Pain associated with the bladder
• Urinary urgency

Absence of any of the following criteria, which would exclude the diagnosis:

• Cystometric bladder capacity larger than 350 mL in a conscious subject with either gas or liquid filling
• Intense urge to void when patient's bladder has been filled with 100 mL of gas or 150 mL water during cystometry at a fill rate of 30-100 mL/min
• Demonstration of phasic involuntary bladder contractions on cystometry findings at a fill rate of 30-100 mL/min (Note that although this is an exclusion criterion as per the NIDDK, detrusor instability may be present in as many as 14% of patients with a clinical diagnosis of IC.)
• Duration of symptoms less than 9 months
• Nocturia
• Symptoms relieved by antimicrobials, urinary antiseptics, anticholinergics, or antispasmodics
• Frequency of micturition of less than 8 times per day
• Diagnosis of bacterial prostatitis or cystitis within a 3-month period
• Presence of ureteral or bladder calculi
• Active genital herpes
• Uterine, cervical, vaginal, or urethral cancer
• Urethral diverticulum
• Cyclophosphamide or other chemical cystitis
• Tuberculous cystitis
• Radiation cystitis
• Benign or malignant bladder tumors
• Vaginitis
• Patient younger than 18 years

INDICATIONS

Section 3 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Because no discrete pathognomonic pathologic criteria exist for assessing and monitoring disease severity, indications and goals for treatment are based on the degree of patient symptoms. Assessing patient response to treatment is also complicated because of the subjective nature of symptoms and the lack of objective serological, physical, or histopathological findings. Conservative measures and oral or intravesical treatments are considered first-line treatment.

Indications for surgical intervention in interstitial cystitis (IC) are limited to (1) cystoscopy for both diagnosis and therapeutic purposes, (2) neuromodulation for urgency or frequency symptoms, and (3) urinary reconstruction, (4) urinary diversion, or both for the rare patient who may benefit from these procedures. Botulinum toxin type A is an emerging therapy for many urologic diseases associated with frequency, urgency, and urge incontinence but is still considered investigational in the treatment of IC.

Although somewhat controversial, cystoscopy under anesthesia and bladder overdistension, with or without bladder biopsy, is used by many physicians as an initial diagnostic procedure. A diminished bladder capacity under anesthesia and/or a Hunner ulcer (very rare) are suggestive (and some feel diagnostic) of IC. Furthermore, relief of urinary frequency, urgency, and pain has been reported, at least temporarily, in as many as 60% of patients following bladder overdistension. However, note that initially, many patients find that their symptoms are transiently exacerbated following this procedure.

Bladder biopsy is performed to evaluate for carcinoma in situ (CIS) and the presence of mast cells. Some authors have proposed a pathophysiological role for mast cells in the genesis of IC and have suggested that an increased density of mast cells may be present in patients with IC. Furthermore, the finding of mast cells may suggest a potential role for antihistamine compounds in the treatment of the condition.

Direct sacral nerve root stimulation, or neuromodulation, has been shown to be effective in treating frequency and urgency associated with IC. In patients taking chronic narcotics for refractory pain associated with IC, sacral neuromodulation has been shown to decrease (but not eliminate) narcotic requirements after implantation.

Indications for urinary tract reconstruction or diversion are very limited in patients with IC. Candidates for these procedures should have exhausted all reasonable and available medical, pharmacological, and behavioral therapies for their condition. They should also understand that even technically successful urinary tract reconstruction or urinary diversion still may not relieve the underlying symptoms of pain and urinary urgency. These are large surgical undertakings and, for the most part, are irreversible. Only limited success has been reported, thus, patients should be extensively counseled prior to undergoing this type of surgical therapy for IC.

RELEVANT ANATOMY

Section 4 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Abdominal, pelvic, and directed neurologic examinations should be performed in all patients with voiding dysfunction; nevertheless, the findings from these examinations often are unrevealing in patients with interstitial cystitis (IC). Women with IC may express some discomfort with palpation over the urethra and bladder base. A correlation has been noted between urethral tenderness and the finding of a Hunner ulcer after cystoscopic examination.

Pain upon urethral palpation in the presence of an anterior vaginal wall mass may suggest urethral diverticulum, whereas cervical motion tenderness may suggest pelvic inflammatory disease. Examination with a speculum may reveal prolapse; masses; and evidence of vaginitis, herpes, vestibular adenitis, vulvovestibulitis, vulvodynia, or other pathology. These findings suggest a diagnosis other than IC.

Palpation for a full bladder and bimanual examination evaluating for adnexal masses should be part of the complete examination. Rectal examination should always be performed to evaluate for masses, tenderness, and assessment of rectal and pelvic floor (levator) muscle tone.

Neurologic examination findings are usually unremarkable, but abnormalities of motor function, sensation, or reflexes may indicate spinal cord or nerve root dysfunction and should prompt further evaluation for other diagnoses.

Male patients commonly have no abnormalities upon examination. In male patients with irritative lower urinary tract symptoms, bladder outlet obstruction and chronic nonbacterial prostatitis are important diagnostic considerations.

CONTRAINDICATIONS

Section 5 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Contraindications to cystoscopy and bladder hydraulic distension include anesthetic risk, history of prior rupture during distension, pregnancy, and urinary tract infection (UTI).

WORKUP

Section 6 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Lab Studies

• No urine cytology findings specifically suggest a diagnosis of interstitial cystitis (IC).
• • A voided or catheterized urine specimen demonstrating cytologic changes consistent with dysplasia, carcinoma in situ (CIS), or frank cancer should prompt immediate further urologic evaluation.
  • Urinalysis results are usually normal. Microscopic hematuria and pyuria are present in some patients. By definition, urine culture results should be negative.
  • Urethral and vaginal culture results also must be negative for pathologic organisms (eg, fungi and gonorrheal, chlamydial, and trichomonal species).
  • Findings from other urine studies, such as voided cytology or bladder lavage cytology, may help exclude other diagnoses such as CIS and transitional cell carcinoma.
• No serologic or hematologic abnormalities are known to be specific for IC.
• • Various assays for stress protein genes, glycosaminoglycans, mast cell tryptase, Tamm-Horsfall protein autoantibodies and others are suggested by a number of investigators; however, these assays are presently used primarily for research purposes and do not have a defined role in the diagnosis of IC.
  • In men, expressed prostatic secretions yield no findings specific for IC; nonetheless, localizing cultures and microscopic examination should be performed to exclude bacterial prostatitis.
• Much research is being undertaken to identify urine markers expressed in patients with IC to develop a noninvasive laboratory test.
• • Keay et al has reported that urine samples in patients with IC contain a factor (antiproliferative factor, or APF) that inhibits bladder epithelial growth. They also found that APF influences changes in specific levels of bladder epithelial growth factors including significantly decreased levels of heparin-binding epidermal growth factor (HB-EGF) and increased levels of epidermal growth factor (EGF) in patients with IC compared to normal controls and patients with other urogenital diseases.
  • The sensitivity and specificity of APF activity, decreased HB-EGF levels, and increased EGF levels in patients with IC compared with control groups was 94% and 95%, 93% and 89%, and 87% and 91%, respectively. The results are promising, but these assays are currently experimental and are not commercially available.

Imaging Studies

• No known radiographic, ultrasonographic, or other imaging findings are specific for IC.
• Unless indicated to help exclude alternative diagnoses, radiographic studies have only a limited role in the evaluation of IC. Cross-sectional imaging, including MRI, CT scan, and pelvic sonography, may be performed when clinically indicated to evaluate for a suggestive pelvic mass that is causing compression of the bladder or for an adjacent inflammatory process (eg, diverticulitis).
• Cystography and voiding cystourethrography may be used to evaluate the bladder for other causes of irritative lower urinary tract symptoms, including intravesical masses, stones, bladder diverticula, urethral diverticula, urethral stricture, meatal stenosis, or findings suggestive of a neurogenic or nonneurogenic voiding dysfunction.

Other Tests

• Urodynamic studies are not part of the routine IC evaluation.
• • Few urodynamic findings are consistent in patients with IC, and findings specific for the syndrome do not exist.
  • With filling cystometry, most patients have a hypersensitive bladder with a small volume at first sensation to void and also at capacity. Pain with bladder filling that reproduces the patients' IC symptoms is very supportive of a diagnosis of IC.
  • Bladder compliance in patients with IC is normal.
  • The prevalence rate of involuntary bladder contractions in patients with IC symptoms is approximately 14%; however, when observed on filling cystometry studies, bladder contractions are commonly cited as mitigating evidence against a diagnosis of IC, as per the NIDDK criteria.
  • Volitional bladder contractions in patients with IC are quite similar to those in healthy persons.
  • Findings from pressure flow studies and free uroflow studies are usually unremarkable.
  • Sphincter electromyography findings may show some increased activity caused by pain with bladder filling. True detrusor-sphincter dyssynergia excludes the diagnosis of IC. Postvoid residual volume should be minimal.
• Biopsies are primarily performed to help rule out other varieties of cystitis and malignant or premalignant (CIS) lesions. They are also performed to evaluate for detrusor mastocytosis.

Diagnostic Procedures

• Endoscopic findings: Aside from a thorough history and physical examination, cystoscopy is described as the most important diagnostic tool for assessing a patient who may have IC.
• • Cystoscopy is performed to help exclude other causes of symptoms suggestive of IC and to provide evidence for the diagnosis of IC. Sometimes, cystoscopy is performed without anesthesia; however, bladder hypersensitivity with filling and pelvic pain may limit the examination considerably. Importantly, patients who can tolerate several hundred milliliters of fluid during bladder filling, with manipulation and examination, without general anesthesia probably do not have IC.
  • In general, cystoscopy is performed while the patient is under anesthesia in order to provide sufficient distension to examine for coexisting urethral and bladder pathology (eg, transitional cell carcinoma) and features of IC such as Hunner ulcers and glomerulations. Bladder capacity values are also recorded.
• Diagnostic hydrodistention (ie, overdistension): This is performed by placing the irrigation fluid at 80-100 cm water above the patient's bladder. Fluid is run into the bladder under gravity until it slows to a drip. Manual compression of the urethra around the cystoscope sheath should be performed as the bladder fills to help prevent the egress of fluid and to ascertain the true bladder capacity.
• • Continuous intravesical observation of the bladder wall is necessary to note perforation and extravasation as the bladder is filled. A seemingly large bladder capacity or exceedingly prolonged filling time without deceleration of the filling rate may indicate bladder perforation.
  • Examination of the fully distended bladder should be unremarkable, except for perhaps some mild trabeculation. The diagnostic distension is typically held for 1-2 minutes, and then the bladder is drained. The amount of drainage (bladder capacity under anesthesia) and the color of the effluent are recorded. Characteristically, the last 50-100 mL of effluent may be blood tinged (terminal pinking) in patients with IC.
  • The bladder capacity may be reduced in patients with the classic or ulcer variety of IC, whereas the bladder capacity is normal or only slightly reduced in patients with the nonulcerative form of IC.
  • Reinspection of the bladder may reveal diffuse pinpoint petechial hemorrhages within the bladder (ie, glomerulations). These lesions are small, hemorrhagic, and raspberrylike in appearance and are graded as mild, moderate, or severe based on severity. Glomerulations represent the most constant finding after cystoscopy in patients with IC. Typically, the glomerulations are present in at least 3 quadrants of the bladder, sparing the trigone. These glomerulations may appear in a checkerboardlike or latticelike configuration or may appear as splotchy areas over a section of the bladder. Glomerulations noted only along the posterior wall suggest trauma from the cystoscope sheath and not necessarily any pathologic process such as IC.
  • Glomerulations are not specific for IC, although some authors state that glomerulations are not present in healthy bladders. Others have speculated that the appearance of glomerulations may simply be a manifestation of chronic bladder underfilling due to hypersensitivity or sensory urgency rather than any specific primary pathologic process such as IC. Glomerulations may also develop in various other bladder conditions, including neoplasia, infectious cystitis, radiation cystitis, and chemical cystitis, and in patients with a defunctionalized bladder (patients on dialysis) and other conditions in which the bladder has been chronically underfilled (eg, patients who have undergone urinary diversion).
  • The classic description of IC is a reddened bladder with a reduced capacity and fissures and scars that crack and bleed after distension. These findings with the classic Hunner ulcer are exceedingly rare. Mucosal cracks, ulcers, and fissures are much more common than the classic Hunner ulcer. Most patients with IC have a normal bladder capacity (>400 mL), some degree of glomerulations, and terminal pinking following hydrodistention. The finding of a Hunner ulcer should be noted with caution because previous biopsy or transurethral resection sites sometimes can appear quite similar to a Hunner ulcer. Hunner ulcers are discreet patches of denuded (ie, ulcerated) bladder wall, which are thought to be highly specific for the diagnosis of IC. Unfortunately, these are observed in fewer than 10% of patients.
  • In general, the cystoscopic findings, including severity of glomerulations and amount of bleeding, do not correlate with symptom severity or treatment response.
• In summary, endoscopic features of IC prior to hydrodistention include a normal urethral lumen, Hunner ulcers (rare), and an absence of lesions or masses (intrinsic or extrinsic) suggestive of other pathology or disease processes. Following hydrodistention to 80 cm water pressure for 1-2 minutes, the following may be identified: (1) glomerulations (petechial hemorrhages), (2) submucosal hemorrhages, and (3) bloody effluent upon drainage (terminal pinking). In classic or ulcerative IC, observed in approximately 10% of patients, decreased bladder capacity (<400 mL), ulcers, or scars may be seen. In nonulcerative disease (90%), bladder capacity is usually more than 400 mL and ulcers, scars, or mucosal cracking are usually absent.
• Potassium sensitivity test: Some authors have found that certain subgroups of patients with IC have increased urothelial permeability to certain intravesical constituents. This potential property is exploited in the potassium sensitivity test as a diagnostic test for IC.
• • In patients with IC or other conditions of the bladder that affect urothelial permeability, the patient experiences acute and severe pain with intravesical instillation of the potassium chloride solution. Patients who do not have IC experience little or no pain from the solution.
  • This test is controversial because its operating characteristics (eg, sensitivity, specificity) have not been clearly defined. It has not been widely adapted for clinical use.

Histologic Findings

No pathonomic histologic findings exist for IC.

TREATMENT

Section 7 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Medical therapy

The therapy for interstitial cystitis (IC) begins with extensive patient education regarding the chronic nature of the disease and realistic assessments of the condition, prognosis, and potential responses to therapy. Ongoing reassurance and physical and emotional support are important as the diagnostic evaluation progresses and therapies are applied. Only rarely will patients with IC have an immediate, complete, and durable response to any particular therapy. They must be counseled at length regarding the lack of universally effective therapies. Often, referral to one of the local IC support groups, especially a local chapter of the Interstitial Cystitis Association, can be helpful in providing a continuing network of support for the patient.

Ideally, in clinical practice, the treatment of IC should be initiated with the least invasive, least expensive, and most reversible therapy. In general, this consists of a program of dietary and fluid management, time and stress management, and behavioral modification. Thereafter, treatments are applied in a progressively more invasive step-wise fashion until some degree of symptomatic relief is obtained.

Interventions might include various pharmacological agents (eg, sodium pentosan polysulfate [Elmiron], antihistamines, tricyclic antidepressants, analgesics, anti-inflammatory agents), intravesical therapy (ie, medications intermittently instilled directly into the bladder via a catheter), electrical stimulation, and complementary therapies such as acupuncture and hypnosis.

Following each intervention, the patient is reassessed for response. Unfortunately, therapies are often applied in a haphazard "hit-and-miss" fashion, combining a number of different therapies before truly assessing the patient's response to each therapy. This approach is sometimes partly driven by unrealistic patient demands and expectations regarding the success of various therapeutic interventions. Again, patients must receive extensive counseling regarding the nature and prognosis of their condition and its response to therapy. This is critically important, and such counseling must be initiated prior to embarking on invasive interventions for which no proven overwhelming benefit may be achieved.

Biofeedback and pelvic floor rehabilitation (ie, Kegel exercises), bladder training programs (ie, progressively increasing the voiding interval over the course of weeks to months), and other behavioral measures are excellent initial interventions and have been used by some authors with some success. The urinary frequency and urgency components seem to respond better to these interventions than the pelvic pain component.

Various dietary measures have been examined as therapy of IC. These dietary measures and the previously mentioned behavioral measures can be effective when used alone, but can also be complementary to virtually all other interventions for IC. Certain foods, including coffee, alcohol, tomatoes, vinegar, spicy foods, chocolate, and particular fruits and vegetables, have been implicated in aggravating symptoms of IC and, in the opinion of some authors, can precipitate symptomatic flares. Avoiding these food items or substituting other food items is often advised. Not uncommonly, patients are instructed to fill out a food diary, recording the relationship between the consumption of various food and drink items and their IC symptoms. In this manner, items that provoke or exacerbate the IC symptom complex can be eliminated from the diet in a methodical fashion.

Ultimately, the decision to abandon or augment behavioral therapy and pursue other therapeutic options is made by both the patient and physician when a general lack of progress occurs or when symptoms progress. Very few, if any, studies have looked at the minimal duration of time necessary to assess response to behavioral therapy in patients with IC. Furthermore, an optimal behavioral program has also not been defined. Given the chronic nature of the condition and the possibility of spontaneous improvement or remission, progressively more invasive and expensive treatment should be initiated with caution. Generally, if tolerated by the patient, a trial of 3-6 months of behavioral therapy is warranted prior to proceeding to more invasive or expensive therapies.

Managing the pain component can be difficult in patients with IC. The etiology of the pain remains unclear in patients with IC, but the etiology has been postulated by various authors to be mediated centrally, peripherally, or locally, via a neurogenic or inflammatory mechanism. Some patients require pain medications for the long-term, while others rely on these only during periods of symptomatic flares. Anti-inflammatory agents, acetaminophen, Neurontin, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and various other agents are used. Most clinicians tend to avoid the extensive use of narcotics in patients with IC. When the pain component becomes unresponsive to nonnarcotic agents, referral to a chronic pain management facility may be helpful.

Transcutaneous electrical nerve stimulation (TENS) units, electrical stimulation (intravaginal), acupuncture, and intrathecal and intraspinal infusions have all been used. Topical anesthetics such as lidocaine have been applied directly to the bladder via the intravesical route and have achieved some success.  

Raymond Rackley, MD, from the Cleveland Clinic, has developed an intravesical formula that they have found to be highly successful in otherwise resistant or difficult cases. They use 50 mL of 1% lidocaine solution, in which they dissolve one tablet of sodium bicarbonate (650 mg), a 100-mg tablet of Elmiron, and a 200-mcg tablet of misoprostol (Cytotec), a synthetic prostaglandin E1 analog. This is allowed to sit for 1 hour and is then instilled into the bladder through a catheter; the patient is asked to retain it for as long as possible. The procedure is repeated as often as necessary to achieve relief, typically starting at 3-4 times per day in severe cases. 

Oral medications should be considered only after the aforementioned conservative measures have failed. With the exception of Elmiron, the drugs listed in Medications are not specific for the treatment of IC; however, all of them have demonstrated some degree of efficacy in controlled or uncontrolled studies. The duration of individual pharmacotherapy is variable. The clinical studies on Elmiron seem to suggest that maximal effects are not observed until the patient has been on drug therapy for 5-6 months. Other medications are dispensed and their effects are reevaluated as per the expected pharmacokinetics. For example, steady-state serum levels of many tricyclic antidepressants are not attained until 6-8 weeks of stable dosing. Only at this time can the drug dose be safely and reasonably adjusted.

A National Institutes of Health (NIH)–funded study compared placebo with oral pentosan polysulfate sodium (PPS), hydroxyzine, and a combination of both. Using PPS alone or in combination with hydroxyzine was shown to be slightly beneficial, but this was not significant.

In a randomized, double-blind, placebo-controlled study, amitriptyline has been shown to provide statistically significant improvement in the O'Leary-Sant IC symptom and problem index, pain, and urgency intensity when compared to placebo. Common adverse effects include dry mouth, weight gain, constipation, and sedation.

Anticholinergic agents such as oxybutynin and tolterodine can be used to treat the urinary frequency component of the condition; however, these agents can impair bladder emptying and thus may exacerbate pelvic pain. They should be used with caution in patients with IC.

The authors' algorithm for treatment is largely based on whether the patient has predominantly a pelvic pain component or an urgency/frequency component. In the authors' experience, patients with pelvic pain and minimal voiding symptoms represent a pharmacological challenge, making an early pain clinic referral a useful adjunct.

In patients with significant voiding symptoms, the authors suggest an algorithm proposed by Hanno. Conservative treatment may include patient education, dietary manipulation, nonprescription analgesics, and pelvic floor relaxation. If an improvement in symptoms is inadequate, begin oral therapy with either antispasmodics and nonnarcotic analgesics or with amitriptyline for 8 weeks. If amitriptyline fails, a trial of hydroxyzine for 8 weeks is suggested. If no response is observed, follow hydroxyzine with sodium pentosan polysulfate (Elmiron).

A 6- to 9-month course of Elmiron (100 mg tid) is followed by a reassessment of IC symptoms. The authors have found that lower doses of this compound are not as effective but have not used the higher doses advocated by some authors. In the authors' experience, the better plan is to try single-agent therapy first, moving down the ladder of medications, rather than treating patients with multiple agents from the outset. If conservative measures and medical therapy fail to provide adequate relief, surgical therapy should be considered.

Although IC has been reported in children, the condition is observed almost exclusively in adults; therefore, pediatric dosages are not included.

Medications

Drug Category: Antihistamines - These agents inhibit binding to H1 histamine receptor.

Drug Category: Antidepressant, tricyclic - These agents increase the synaptic concentration of serotonin and/or norepinephrine in the CNS.

Other agents used with less success include L-arginine, nalmefene, anticholinergic agents (eg, oxybutynin, oxybutynin XL, tolterodine [Detrol and Detrol LA]), hyoscyamine] corticosteroids, antispasmodics, immunosuppressives, anti-inflammatories, and calcium channel blockers. In addition, a recent report suggests a beneficial role for oral cimetidine. Intravesical agents include the following:

Drug Category: Renal and Genitourinary Agents - These agents are used for the symptomatic relief of interstitial cystitis.

Drug Category: Cauterizing agents - These agents are used for the removal of granulation tissue.

Drug Category: Dermatological Agents - These agents are used for their cleansing and disinfection and for the removal of necrotic debris.

Drug Category: Polysaccharide glycosaminoglycans - These agents may exert a protective effect on the bladder.

Patients in whom medical therapy fails may benefit from another bladder hydrodistention if the first hydrodistention was therapeutic earlier. When Hunner ulcers are identified, laser fulguration has been shown to be therapeutic. If patients still do not respond, intravesical therapy may be initiated, beginning with weekly DMSO therapy for 6 courses. Monthly maintenance DMSO instillations have been advocated by some clinicians in order to prevent flares, although data supporting this approach are lacking. DMSO may be combined with steroids, bicarbonate, and heparin. Intravesical lidocaine also may be added. Some patients with refractory IC symptoms self-catheterize at home and instill a variety of these medications intravesically on an as-needed basis for symptom flares or simply for long-term therapy. In patients who respond poorly to DMSO, intravesical heparin or Clorpactin may be tried.

Chronic application of capsaicin, a component of hot pepper, has been associated with the desensitization of C fibers, the unmyelinated nerve fibers known for transmitting pain. Intravesical instillation of capsaicin has been limited in its use in IC because of the sensation of severe burning; however, resiniferatoxin, a capsaicin analogue, is 100-10,000 times more potent than capsaicin and is not associated with severe burning. Resiniferatoxin has shown a significant reduction in pain, urgency, and nocturia after one installation, holding great promise for future use, but is currently not commercially available.

Patients in whom all forms of noninvasive therapy fail, including a referral to a pain clinic, should be considered candidates for sacral neuromodulation or other investigational protocols.

Surgical therapy

Bladder hydraulic distension

Following diagnostic hydrodistention, a therapeutic hydrodistention may be performed. This usually is performed at 80-100 cm water for 8-10 minutes.

After draining the bladder from the therapeutic hydrodistention, bladder biopsy may be performed on areas that appear abnormal. Biopsy should be deep enough to sample the detrusor muscle. Unfortunately, no pathognomonic histological findings exist for IC. Biopsies primarily are performed to help rule out other varieties of cystitis or malignant or premalignant (eg, carcinoma in situ [CIS]) lesions. In all cases, biopsy should be performed following hydrodistention.

In the authors' opinion, postoperative catheter drainage should be instituted in patients who have deep biopsies to reduce the chance of perforation, extravasation, or both. Although some centers advocate limiting the use of cystoscopy and biopsy in the evaluation and workup of patients thought to have IC, the authors believe these are necessary to help exclude other disorders such CIS and bladder calculi.

The mechanism of action of bladder hydraulic distension is unknown. Hypotheses include neurapraxias by mechanical trauma and epithelial damage from mechanical trauma.

Emerging surgical therapies

Sacral neuromodulation has been approved by the US Food and Drug Administration (FDA) for medically refractory frequency, urgency, and urge incontinence and is showing promising results in patients with IC. Several authors have studied sacral neuromodulation in patients with IC refractory to conservative measures (behavioral modification, diet, medications, hydrodistention). Sacral neuromodulation improved daytime frequency, nocturia, and mean voided volumes and decreased pain and IC symptom and problem index scores. In addition, sacral neuromodulation has been shown to normalize the abnormally high levels of antiproliferative factor (APF) and the abnormally low levels of heparin-binding epidermal growth factor (HB-EGF) in the urine of patients with IC.

Transurethral intradetrusor injection of botulinum A toxin is being investigated for use in patients with neurogenic and nonneurogenic causes of urinary frequency, urgency, and urge incontinence due to detrusor overactivity. Many patients show remarkable subjective improvement in incontinence after botulinum A toxin injection, but the effect wanes after 3 months. The use of intradetrusor botulinum A toxin is still investigational, but early results are encouraging.

Rarely indicated surgical therapies

• Laser photoradiation (poor results)
• Electrical stimulation
• TENS (more marked effect on bladder pain than on urinary frequency)
• Peripheral denervation (rarely indicated)
• Bladder augmentation (controversial results because pain component does not improve in most patients)
• Urinary diversion (most invasive, usually reserved as last resort)

Follow-up

No established guidelines exist for monitoring patients with IC. This is not surprising given the wide spectrum of severity of patient symptoms.

For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Urinary Tract Infections.

COMPLICATIONS

Section 8 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Although rare, classic interstitial cystitis (IC) may lead to bladder wall scarring that results in a contracted small-capacity bladder. These patients often require augmentation cystoplasty or some form of urinary diversion.

Other long-term sequelae of IC are unknown. However, due to the chronic nature of the condition and the significant impact on the patient's quality of life, the psychological impact of the condition can be enormous. Ongoing emotional support is essential.

OUTCOME AND PROGNOSIS

Section 9 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Interstitial cystitis (IC) is a chronic condition with a variable course, which, unfortunately, responds poorly to treatment in many cases. The most important element in treating these patients is education and emotional support. Patients must understand that the disease is characterized by intermittent periods of exacerbations and remissions. Periodic exacerbations are managed as they occur because no long-term therapy has been shown to prevent or delay recurrent episodes. Furthermore, even though only approximately 10% of patients manifest classic or ulcerative IC, no treatment to date has been shown to decrease disease progression; therefore, the purpose of treatment is to palliate and alleviate symptoms.

FUTURE AND CONTROVERSIES

Section 10 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

Diagnosing interstitial cystitis (IC) remains difficult even more than 100 years after it was described by Skene in 1887. No pathognomonic findings exist with regard to patient history, physical examination findings, laboratory findings, or cystoscopy findings. The exclusion of other clinical entities remains the foremost goal of the workup and evaluation of patients thought to have this condition.

A careful, complete, and empathetic history and physical examination are critical. Cystoscopy is an adjunctive, although important, study. The classic Hunner ulcer in the setting of a small-capacity bladder (ie, assessed under anesthesia) rarely confirms the diagnosis with certainty. Until IC is defined completely or a definitive marker becomes universally available, the diagnosis remains one of exclusion.

Studies at several centers are examining various soluble urinary and serum markers in patients with IC. The goals of this research include identifying the causative agent(s) or at least a marker for case identification and diagnosis. Alternatively, certain other soluble factors are being evaluated as potential surrogates of disease activity and response to therapy.

Ongoing studies are investigating the use of intravesical bacille Calmette-Guérin vaccine (ie, an attenuated form of tuberculous bacterium used to treat some forms of bladder cancer) for the treatment of IC. Neuromodulation using implantable stimulators is also being evaluated as a therapy for chronic refractory IC.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome And Prognosis
• Future And Controversies
• References

• Alagiri M, Chottiner S, Ratner V, et al. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology. May 1997;49(5A Suppl):52-7. [Medline].
• Badenoch AW. Chronic interstitial cystitis. Br J Urol. Dec 1971;43(6):718-21. [Medline].
• Chai TC, Zhang C, Warren JW, Keay S. Percutaneous sacral third nerve root neurostimulation improves symptoms and normalizes urinary HB-EGF levels and antiproliferative activity in patients with interstitial cystitis. Urology. May 2000;55(5):643-6. [Medline].
• Chaiken DC, Blaivas JG, Blaivas ST. Behavioral therapy for the treatment of refractory interstitial cystitis. J Urol. Jun 1993;149(6):1445-8. [Medline].
• Close CE, Carr MC, Burns MW, et al. Interstitial cystitis in children. J Urol. Aug 1996;156(2 Pt 2):860-2. [Medline].
• Comiter CV. Sacral neuromodulation for the symptomatic treatment of refractory interstitial cystitis: a prospective study. J Urol. Apr 2003;169(4):1369-73. [Medline].
• Flynn MK, Webster GD, Amundsen CL. The effect of botulinum-a toxin on patients with severe urge urinary incontinence. J Urol. Dec 2004;172(6 Pt 1):2316-20. [Medline].
• Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29, 1987. J Urol. Jul 1988;140(1):203-6. [Medline].
• Hanno P. Interstitial cystitis and related diseases. In: Walsh PC, Wein AJ, Retik AB, Vaughan ED, eds. Campbell's Urology. 7^th ed. Philadelphia, Pa: WB Saunders; 1997:631-62.
• Hanno P, Keay S, Moldwin R, Van Ophoven A. International Consultation on IC - Rome, September 2004/Forging an International Consensus: progress in painful bladder syndrome/interstitial cystitis. Report and abstracts. Int Urogynecol J Pelvic Floor Dysfunct. Jun 2005;16 Suppl 1:S2-S34. [Medline].
• Hanno PM. Diagnosis of interstitial cystitis. Urol Clin North Am. Feb 1994;21(1):63-6. [Medline].
• Held PJ, Hanno PM, Wein AJ. Epidemiology of interstitial cystitis. In: Hanno PM, Staskin DR, Krane RJ, Wein AJ, eds. Interstitial Cystitis. New York, NY: Springer-Verlag; 1990:29-48.
• Hunner GL. A rare type of bladder ulcer in women: Report of cases. J Boston Med Surg. 1915;172:660-5.
• Keay SK, Zhang CO, Shoenfelt J, et al. Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor as urine markers for interstitial cystitis. Urology. Jun 2001;57(6 Suppl 1):9-14. [Medline].
• Koziol JA, Clark DC, Gittes RF, Tan EM. The natural history of interstitial cystitis: a survey of 374 patients. J Urol. Mar 1993;149(3):465-9. [Medline].
• Messing EM. The diagnosis of interstitial cystitis. Urology. Apr 1987;29(4 Suppl):4-7. [Medline].
• Moldwin RM, Sant GR. Interstitial cystitis: a pathophysiology and treatment update. Clin Obstet Gynecol. Mar 2002;45(1):259-72. [Medline].
• Nigro DA, Wein AJ. Interstitial cystitis: Clinical and endoscopic features. In: Sant GR, ed. Interstitial Cystitis. ed. Philadelphia, Pa: Lippincott-Raven; 1997:137-42.
• Oravisto KJ. Epidemiology of interstitial cystitis. Ann Chir Gynaecol Fenn. 1975;64(2):75-7. [Medline].
• Ottem DP, Teichman JM. What is the value of cystoscopy with hydrodistension for interstitial cystitis?. Urology. Sep 2005;66(3):494-9. [Medline].
• Parsons CL, Boychuk D, Jones S, et al. Bladder surface glycosaminoglycans: an epithelial permeability barrier. J Urol. Jan 1990;143(1):139-42. [Medline].
• Peters KM, Konstandt D. Sacral neuromodulation decreases narcotic requirements in refractory interstitial cystitis. BJU Int. Apr 2004;93(6):777-9. [Medline].
• Rackley RR. Intravesical instillation for interstitial cystitis. Personal Communication. March 2007.
• Rajkumar GN, Conn IG. Botulinum toxin: a new dimension in the treatment of lower urinary tract dysfunction. Urology. Jul 2004;64(1):2-8. [Medline].
• Rapp DE, Lucioni A, Katz EE, et al. Use of botulinum-A toxin for the treatment of refractory overactive bladder symptoms: an initial experience. Urology. Jun 2004;63(6):1071-5. [Medline].
• Rosenberg MT, Hazzard M. Prevalence of interstitial cystitis symptoms in women: a population based study in the primary care office. J Urol. Dec 2005;174(6):2231-4. [Medline].
• Sant GR. Interstitial cystitis. Monogr Urol. 1991;12:37-63.
• Sant GR, Propert KJ, Hanno PM, et al. A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol. Sep 2003;170(3):810-5. [Medline].
• van Ophoven A, Pokupic S, Heinecke A, Hertle L. A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol. Aug 2004;172(2):533-6. [Medline].
• Warren JW, Keay SK, Meyers D, Xu J. Concordance of interstitial cystitis in monozygotic and dizygotic twin pairs. Urology. Jun 2001;57(6 Suppl 1):22-5. [Medline].
• Zolton E, Ferlise V, Hanno PM. Painful Bladder Syndrome/Interstitial Cystitis. AUA Update Series. 2006;25 (9):78-87.

Article Last Updated: May 3, 2007