Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis

Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis

Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Sandy J Falk, MD



Last literature review version 16.2: May 2008 | This topic last updated: June 3, 2008 (More)


INTRODUCTION — Painful bladder syndrome/interstitial cystitis (PBS/IC) is a disorder characterized by bladder pain of variable severity, lasting over a protracted period of time. It can affect women or men, but is more common in women. The diagnosis and treatment of PBS/IC are controversial, similar to other enigmatic medical conditions of unknown origin that are difficult to treat.

The diagnosis and etiology of PBS/IC will be discussed here. Treatment of this disorder is reviewed separately. (See "Treatment of painful bladder syndrome/interstitial cystitis").

DEFINITION — Definitions of IC have widely varied over the past few decades. Before 2002, IC was defined in research settings according to the criteria of the National Institute for Diabetes and Diseases of the Kidney (NIDDK), the so-called "NIDDK criteria" (show table 1) [1] . The NIDDK criteria were soon recognized as being too restrictive for general use; therefore, in 2002 the International Continence Society (ICS) published new recommendations for definition of the painful bladder disorders (show table 1) [2] . Although this definition has been recognized as having some limitations, it is widely used. The ICS defines PBS as a clinical syndrome (ie, a complex of symptoms) consisting of "suprapubic pain related to bladder filling, accompanied by other symptoms, such as increased daytime and nighttime frequency in the absence of proven infection or other obvious pathology." By comparison, the term "interstitial cystitis (IC)" is reserved for patients who have PBS symptoms, but who also demonstrate "typical cystoscopic and histological features" during bladder hydrodistension.

In 2006, the European Society for the Study of IC/BPS (ESSIC) proposed yet another system that is likely to become popular (show table 1) [3] . The diagnosis of Bladder Pain Syndrome (BPS), distinct from PBS, is based upon the presence of pain related to the urinary bladder and accompanied by at least one other urinary symptom. Diseases that cause similar symptoms need to be excluded and cystoscopy with hydrodistension and biopsy (if indicated) should be performed. The ESSIC suggest avoiding the term IC, and instead using the term BPS, followed by a grade denoting severity of cystoscopic appearance and severity of biopsy findings (if performed).

It is likely that further refinement of terminology will occur during the coming years.

PREVALENCE — Because of variable diagnostic criteria, reported prevalence rates for PBS/IC vary widely.

Population-based studies report prevalence rates of 10 to 865 cases per 100,000 women [4,5] .

A survey of participants in the United States Nurses' Health Studies suggested a prevalence of 52 to 67 cases per 100,000 women [6] .
The prevalence of physician-diagnosed PBS/IC in a managed care population was 197 cases per 100,000 women and 41 per 100,000 men [7] , but the prevalence of PBS/IC symptoms in the same population was much higher, at 11 percent of women and 5 percent of men [8] .

A Canadian survey of the diagnostic patterns of 65 urologists found that 2.8 percent of patients seen during a two-week period were diagnosed with IC (7.9 percent of female and 0.4 percent of male patients seen in the office, female:male ratio 8:1) [9] .

The estimated clinical prevalence is highest in reports by researchers who believe that many, or even most, women with chronic pelvic pain may actually have IC; as well as those who feel that many men with lower urinary tract symptoms or prostatitis also may have IC and those who use somewhat nonspecific symptom questionnaires to make the diagnosis [10-12] . The "true prevalence" of PBS/IC will only be established when agreement is reached about diagnostic criteria, and a gold standard is available for its diagnosis.

EPIDEMIOLOGY — Studies have consistently found that PBS/IC is more common in women [12] , with a female:male ratio typically reported as 4.5 to 9 females to one male [5,9,13] . The mean age of diagnosis is probably about 42 to 45 years, although symptoms have been recognized in children [4,14,15] . A greater concordance of IC among monozygotic than dizygotic twin pairs suggests a genetic susceptibility to IC [16] .

ETIOLOGY AND PATHOGENESIS — Little is known about the etiology and pathogenesis of PBS/IC. Ongoing and future research will likely demonstrate that patients currently grouped together under the umbrella diagnosis of PBS/IC actually suffer from several distinct conditions with distinct etiologies. Several pathogenetic mechanisms have been proposed to explain the clinical phenomena, and it is accepted that any of several inciting factors may lead to the clinical manifestation of PBS/IC.

Many studies have documented that patients with IC have urothelial abnormalities present in bladder biopsies. Importantly, it is not known whether these urothelial abnormalities represent primary or secondary phenomena (ie, whether the bladder abnormalities are secondary to another process that is yet unrecognized). These abnormalities include: altered bladder epithelial expression of HLA Class I and II antigens, decreased expression of uroplakin and chondroitin sulfate, altered cytokeratin profile (towards a profile more typical of squamous cells), and altered integrity of the glycosaminoglycan (GAG) layer [17-23] . In addition, the expression of interleukin-6 and P2X3 ATP receptors is increased, and activation of the NFkB gene is enhanced.

The GAG layer normally coats the urothelial surface and renders it impermeable to solutes, thus defects in this layer may allow urinary irritants to penetrate the urothelium and activate the underlying nerve and muscle tissues [24] . This process may promote further tissue damage, pain, and hypersensitivity. Bladder mast cells may also play a role in the propagation of ongoing bladder damage after an initial insult [25,26] .

Antiproliferative factor (APF) may also have a pathogenetic role in the generation of PBS/IC symptoms. APF is a sialoglygopeptide that is produced by the urothelium of IC patients, but not by controls without IC [27] . APF may affect urothelial activity through altered production of growth factors and other proteins involved in urothelial growth and function [28] .

It is likely that neurologic upregulation with central sensitization and increased activation of bladder sensory neurons during normal bladder filling plays a role in the generation and maintenance of PBS/IC symptoms [29,30] . This increased sensitivity may be present in the bladder itself, or may be due to increased activity and new pathways within the central nervous system. Animal models suggest that hypersensitivity in bowel and other pelvic organs may be responsible for sensitization of the bladder [31] . Similar alterations in neural pathways may be responsible for the tenderness that is present in PBS/IC patients [32] . It is also possible that the increase in visceral (bladder) sensitivity is secondary to a primary somatic injury that has sensitized central pathways that overlap with afferents from the bladder.

CLINICAL MANIFESTATIONS — The presentation of PBS/IC is variable, but there are many common clinical features [33,34] . All patients with PBS/IC have pain, which is associated with bladder filling and/or emptying, and usually accompanied by urinary frequency, urgency, and nocturia. The pain that is thought to be of bladder origin is usually described as being suprapubic or urethral, although patterns such as unilateral lower abdominal pain or low back pain with bladder filling are not uncommon [35,36] . The severity of pain ranges from mild burning to severe and debilitating.

Increased urinary frequency arises because the pain of bladder filling is partially or completely relieved by voiding, so patients prefer to maintain low bladder volumes. Clinically, it is useful to ask patients why they void frequently to help distinguish PBS/IC from other causes of frequency. As an example, patients with overactive bladder syndrome void frequently to avoid urinary urge incontinence, whereas in PBS/IC they void frequently to avoid discomfort.

Affected patients may also describe chronic pelvic pain that is distinct from their bladder pain, as well as other ongoing, distinct pain symptoms. These patients often carry several diagnoses, such as irritable bowel syndrome (another visceral pain syndrome), dysmenorrhea, endometriosis, vulvodynia, or fibromyalgia [37] . They may also describe exacerbation of their PBS/IC symptoms during times when other pain symptoms are at their worst (eg, "flares" of PBS/IC when irritable bowel syndrome is symptomatic).

The character of symptoms may vary from one day to the next in a single patient. Exacerbation of PBS/IC symptoms may occur after intake of certain foods or drinks (eg, strawberries, oranges, beer, coffee), or during the luteal phase of the menstrual cycle, stressful times, or after activities such as exercise, sexual intercourse, or being seated for long periods of time (eg, a plane trip).

In severe disease, urinary frequency of as many as 60 voids daily may occur, with associated disruptions of daytime activities, and of sleep. Patients may describe sitting on the toilet for hours at a time in order to let urine dribble from their bladders more or less continuously so that bladders remain as empty as possible and pain is minimized. Associated disruption of home and work life, avoidance of sexual intimacy, chronic fatigue and pain, predictably result in some degree of worsening of quality of life in all affected patients. In surveys, 50 percent of patients reported being unable to work full-time, 75 percent described dyspareunia, 70 percent reported sleep disturbance, and 90 percent reported that PBS/IC affected their daily activities [36] .

The majority of patients describe symptoms that are of gradual onset, with worsening of discomfort, urgency and frequency over a period of months. A smaller subset of patients describes symptoms that are severe from their onset. Symptoms of PBS/IC begin suddenly, with some patients able to name the exact date on which symptoms began. In other patients, symptoms begin after an apparently uncomplicated urinary tract infection or surgical procedure, episode of vaginitis or prostatitis, or after a trauma, such as a fall onto the coccyx. In hindsight, these "sentinel events" have often been empirically diagnosed and treated, and usually are themselves somewhat enigmatic.

DIAGNOSTIC EVALUATION — The diagnosis of PBS/IC is based upon the presence of characteristic symptoms, provided that no symptoms or signs of other conditions are present. Confounding conditions, such as genitourinary cancers, urinary tract stones, urinary infection, urinary retention, or pelvic masses, should be excluded by careful history, physical examination, and laboratory tests, as indicated.

Physical examination — A thorough physical examination of patients with PBS/IC is of critical importance in making a diagnosis, and also in treatment planning. On observation, many patients will be tearful and appear fatigued and/or depressed. Variable tenderness of the abdominal wall, hip girdle, soft tissues of the buttocks, pelvic floor, bladder base, and urethra is almost universally present, probably due to sensitization of afferent nerve fibers in the dermatomyotomes (thoracolumbar and sacral) to which the bladder refers. In males, scrotal and penile tenderness can be present.

In some women, adequate speculum and bimanual examination cannot be conducted due to exquisite tenderness of the pelvic tissues. Pelvic ultrasound can be helpful for assessing the pelvic organs in these patients. It is important to remember that allodynia (perception of non-noxious stimuli, such as light touch, as being noxious or painful) can be present in any patient who has been in chronic pain, and that adequate pelvic examination may be impossible in the awake patient. In this situation, clinicians may choose to begin empiric treatment for PBS/IC, and to defer full examination until either symptoms have improved to the point where examination is possible, or until symptoms have failed to respond to usual therapies and the diagnosis must be revisited.

Laboratory tests

Urinalysis with microscopy and urine culture should be performed in all patients to exclude significant hematuria and infection.

Urine cytology and cystoscopy are performed in high risk groups. (See "Epidemiology and etiology of urothelial bladder cancer").

A post-void residual urine volume should be measured, either using a catheter (usually avoided due to associated pain) or by ultrasound.

Examination of the urine for chlamydia is reserved for patients at high risk of sexually transmitted infections. Compliance with standard guidelines for screening for cervical, prostate, and colorectal cancers is important in all patients, including those with painful bladder disorders.

Cystoscopy — Cystoscopy is not mandatory and is typically performed at the discretion of the clinician. In the United States, it is usually reserved for patients with hematuria (gross or microscopic) or with symptoms that raise suspicion for other processes. As an example, synthetic mesh is frequently used for urologic and gynecologic surgery, and mesh erosion into the lower urinary tract has become an increasingly important cause of urinary symptoms. When a patient has a history of pelvic surgery that predates their symptoms, it is important to use cystoscopy to exclude the presence of foreign body in the lower urinary tract. (See "Reconstructive materials in urogynecology: Classification and host response").

Hydrodistension — Hydrodistension of the bladder is not required for diagnosis or treatment of PBS/IC, although strong opinions are voiced on both sides of this issue [38,39] . Patients are placed under anesthesia and the bladder is filled with water or saline until 70 cm of water pressure is reached, usually at a bladder volume that is far greater than the awake-capacity of the patient (eg, 1000 mL). This bladder dilation is maintained for several minutes, then the dilating fluid is released and the bladder is refilled. During this second bladder fill, the bladder epithelium is examined cystoscopically for characteristic findings of IC, which include glomerulations (petechial red areas) and reddened patches (Hunner's patches). Biopsies are taken from any suspicious areas.

Although many medical centers in the United States continue to perform hydrodistension, it has fallen from favor as glomerulations are now considered nonspecific findings (eg, one study found glomerulations in 45 percent of healthy patients [40] ), their presence does not correlate well with symptoms [41] , and the results of hydrodistension do not necessarily affect clinical management.

Bladder biopsy — Bladder biopsy is not required for a diagnosis of PBS/IC, except for exclusion of other disorders. The lack of utility of bladder biopsy was illustrated in a longitudinal study that investigated associations between bladder biopsy features and urinary symptoms in 204 patients with a clinical diagnosis of IC [41] . Only 50 percent of patients demonstrated an increase in mast cell count in the bladder lamina propria (>30 cells per mm(3)), 11 percent demonstrated complete loss of urothelium (ie, an ulcer), 14 percent demonstrated granulation tissue in the lamina propria, and submucosal hemorrhage of varying degree was seen in 67 percent. It is important to note that some of these biopsy findings may have been due to the hydrodistension procedure itself, and that chronic inflammation was present only in a minority of patients.

Findings such as these were behind the impetus to discourage routine use of the term "interstitial cystitis" to describe the clinical syndrome of urinary urgency, frequency and pain, since biopsies suggested that the process is neither "interstitial" nor "cystitis."

Potassium sensitivity test — The potassium sensitivity test (PST) has also been proposed by some researchers as useful for diagnosis of PBS/IC [42] , but is not recommended for routine use since its results are nonspecific for PBS/IC [43] . During this test, 40 mL sterile water is instilled into the bladder, and note is made of any associated pain. The bladder is drained and then filled with a 40 mL of 0.4 M potassium chloride; a finding of increased pain during this second fill is considered indicative of bladder hypersensitivity and suggestive of PBS/IC.

Symptom scales — Some centers use symptom scales to aid in diagnosis of PBS/IC, but in practice, use of these scales adds little to the ability to make a diagnosis and their use is not widespread. However, these scales can be useful in the monitoring of clinical progress after diagnosis [44,45] . Three such scales are the O'Leary-Sant IC symptom and problem index, the Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale, and the University of Wisconsin Interstitial Cystitis Scale [44,46,47] .

Biomarkers — Several biomarkers are being considered as possibly useful for diagnosing PBS/IC. The most promising marker is APF (see "Etiology and pathogenesis" above). In a study in which urine from 219 patients with symptomatic IC was compared with that from 324 controls without IC, the sensitivity and specificity of APF for IC 94 and 95 percent, respectively [27] . Use of APF and other biomarkers requires further validation before they can be recommended clinically.

Urodynamic testing — Urodynamic testing is not currently considered to have a role in the diagnosis of PBS/IC.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Painful bladder syndrome and interstitial cystitis" and see "Patient information: Treatment of painful bladder syndrome and interstitial cystitis"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.

SUMMARY AND RECOMMENDATIONS

Painful bladder syndrome/interstitial cystitis (PBS/IC) refers to a chronic bladder pain syndrome. It is more common in women than men. (See "Definition" above and see "Epidemiology" above).

All patients with PBS/IC have pain, which is associated with bladder filling and/or emptying, and usually accompanied by urinary frequency, urgency, and nocturia. They may also describe chronic pelvic pain that is distinct from their bladder pain, as well as other ongoing, distinct pain symptoms, such as irritable bowel syndrome, dysmenorrhea, endometriosis, vulvodynia, or fibromyalgia. (See "Clinical manifestations" above).

The clinical diagnosis of PBS/IC is based upon the presence of characteristic symptoms, after other conditions with similar symptoms are excluded. (See "Diagnostic evaluation" above).

Physical examination is often remarkable for widespread tenderness of the abdominal wall, hip girdle, buttocks, thighs and pelvic floor, as well as tenderness of the bladder base and/or urethra. (See "Physical examination" above).

Urinalysis with microscopy and urine culture should be performed in all patients to exclude significant hematuria and infection. Cystoscopy, hydrodistension, bladder biopsy, and potassium sensitivity testing are not necessary for diagnosis of PBS/IC. (See "Diagnostic evaluation" above).