Interstitial cystitis/bladder pain syndrome: Clinical features and diagnosis

INTRODUCTION — Chronic bladder pain can be a debilitating condition that impacts quality of life [1]. The pathophysiology of chronic bladder pain is not well understood and symptoms likely represent more than one underlying etiology. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a diagnosis that applies to patients with chronic bladder pain in the absence of other explanatory etiologies. Identification of patients who meet diagnostic criteria for IC/BPS allows for treatment with the goal of providing symptomatic relief. This condition often coexists with other chronic pain syndromes (eg, fibromyalgia, irritable bowel syndrome).

The pathogenesis, clinical features, and diagnosis of IC/BPS will be discussed here. Management of this condition is reviewed separately. (See "Interstitial cystitis/bladder pain syndrome: Management".)

TERMINOLOGY — Chronic bladder pain in the absence of an identifiable etiology has historically been called interstitial cystitis. This term is a misnomer, however, since there is no clear evidence that bladder inflammation (cystitis) is involved in the etiology or pathophysiology of the condition, nor is there evidence that the condition is reliably associated with abnormalities of the interstitium of the bladder.

The understanding is that patients with these symptoms have a chronic pain condition of the bladder, analogous to other poorly understood chronic pain conditions such as fibromyalgia or irritable bowel syndrome. As such, the preferred nomenclature for this constellation of symptoms is painful bladder syndrome or bladder pain syndrome. However, considerable previous efforts have been devoted to recognizing "interstitial cystitis" as a legitimate, disabling medical condition and, therefore, the term has been retained in contemporary use to maintain continuity. This topic review uses the term "interstitial cystitis/bladder pain syndrome."

EPIDEMIOLOGY — Interstitial cystitis/bladder pain syndrome (IC/BPS) is a relatively uncommon condition, although studies likely underestimate the true prevalence. It is more common in women than men and is most often diagnosed in the fourth decade or later [2-4]. Diagnostic criteria for IC/BPS have varied, which has made establishing the prevalence difficult.

Prevalence studies have used one of three methods with differing results:

●Self-report surveys estimate a prevalence of approximately 850 per 100,000 women and 60 per 100,000 men [2].

●Prevalence estimates based on medical billing data are 197 per 100,000 women and 41 per 100,000 men [5].

●The RAND Interstitial Cystitis Epidemiology (RICE) study used a questionnaire of IC/BPS symptoms and surveyed women in approximately 150,000 United States households [6]. They concluded that between 2.7 and 6.5 percent of United States women have symptoms consistent with a diagnosis of IC/BPS.

PATHOGENESIS — Little is known about the etiology and pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS). A greater concordance of IC/BPS among monozygotic twin pairs than among dizygotic twin pairs suggests a potential genetic susceptibility [7,8].

Urothelial abnormalities are present in patients with IC/BPS and may include [9-16]:

●Altered bladder epithelial expression of human leukocyte antigen class I and II antigens

●Decreased expression of uroplakin and chondroitin sulfate

●Altered cytokeratin profile (toward a profile more typical of squamous cells)

●Altered integrity of the glycosaminoglycan (GAG) layer

●A defect in Tamm-Horsfall proteins

●Increased expression of interleukin-6 and P2X3 adenosine triphosphate receptors

●Enhanced activation of the NFkB gene

The GAG layer of the bladder normally coats the urothelial surface and renders it impermeable to solutes. Defects in the GAG layer may allow urinary irritants to penetrate the urothelium and activate the underlying nerve and muscle tissue [17]. 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 [18,19].

Neurologic upregulation of pain sensation likely plays a role in IC/BPS. Central sensitization and increased activation of bladder sensory neurons during normal bladder filling may result in bladder pain [20,21]. 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. Similar alterations in neural pathways may be responsible for the suprapubic tenderness that is present in IC/BPS patients [22]. 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 FEATURES

Symptoms and signs — By definition, all patients with interstitial cystitis/bladder pain syndrome (IC/BPS) have persistent unpleasant sensations attributable to the bladder, of which the most consistent feature is an increase in discomfort with bladder filling and a relief with voiding [23,24]. The distribution of symptoms at time of diagnosis is shown in the table (table 1).

Bladder symptoms are usually described as painful but can include pressure, discomfort, or spasms [24]. Symptoms are usually constant but may vary from one day to the next and range in severity from mild to severe. The location of symptoms is usually described as being suprapubic or urethral, although unilateral lower abdominal pain or low back pain with bladder filling have been observed [25,26].

Symptoms are usually gradual in onset and worsen over a period of months. However, some patients describe symptoms that are abrupt or severe from their onset. Although most patients cannot identify a triggering event, some patients have developed symptoms after an uncomplicated urinary tract infection or surgical procedure, or after a trauma, such as a fall onto the coccyx.

Exacerbation of IC/BPS symptoms may occur after intake of certain foods or drinks, during stress, after certain activities (eg, exercise, sexual intercourse, prolonged sitting), or during the luteal phase of the menstrual cycle [27-29].

Patients may report frequent voiding. However, in contrast to patients with overactive bladder syndrome who void frequently to avoid urinary incontinence, patients with IC/BPS void frequently to maintain low bladder volumes to avoid discomfort [30]. In extreme cases, patients may describe sitting on a toilet for hours 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. Additional urinary symptoms, including urinary urgency and nocturia, may also occur [31]. IC/BPS is not commonly associated with urinary incontinence [31].

On examination, variable tenderness of the abdominal wall, hip girdle, pelvic floor, bladder base, and urethra is almost universally present in patients with IC/BPS. This is likely due to sensitization of afferent nerve fibers in the dermatomes associated with the bladder (thoracolumbar and sacral). In males, scrotal and penile tenderness may be present. Patients with IC/BPS may experience allodynia (perception of non-noxious stimuli, such as light touch, as being noxious or painful) as with other patients with chronic pain. Many patients with IC/BPS also exhibit tenderness or tightness of the pelvic floor muscles [32,33].

Many patients experience disruption of home and work life due to chronic pain, urinary frequency, and fatigue, predictably resulting in some degree of worsening of quality of life [26].

The typical IC/BPS patient will have an unremarkable urinalysis and sterile urine culture, although some may have an occasional positive urine culture because of the frequency of bacteriuria in the general population.

Associated conditions — Other chronic pain symptoms (eg, irritable bowel syndrome, vulvodynia, fibromyalgia) are present in many patients with IC/BPS [34]. Pain associated with these conditions should be differentiated from IC/BPS pain, whenever possible. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults", section on 'Clinical manifestations' and "Vulvar pain of unknown cause (vulvodynia): Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of fibromyalgia in adults", section on 'Symptoms'.)

Sexual concerns and dysfunction are common in women with IC/BPS and may be complicated by the association with vulvodynia as well as the occurrence of bladder-specific symptoms during sexual activity [34-37]. (See "Overview of sexual dysfunction in females: Epidemiology, risk factors, and evaluation", section on 'Risk factors'.)

Men with pelvic pain whether from the bladder (IC/BPS) or elsewhere often also have concomitant sexual dysfunction. (See "Chronic prostatitis and chronic pelvic pain syndrome", section on 'Clinical manifestations'.)

As with other chronic pain syndromes, psychosocial comorbidities are common. (See "Evaluation of chronic non-cancer pain in adults", section on 'Psychiatric comorbidity'.)

EVALUATION

Clinical suspicion — Interstitial cystitis/bladder pain syndrome (IC/BPS) is suspected in patients who have pain perceived to be related to the urinary bladder for several weeks. Usually such patients have already been evaluated for infectious cystitis and either have no evidence of this or have persistent symptoms despite successful treatment. Findings that increase the clinical suspicion for IC/BPS include frequent voiding to avoid discomfort with bladder distension and pelvic tenderness on examination. Tenderness or tightness of the pelvic floor muscles, which can easily be identified by palpation of the levator muscles on pelvic examination in women or on rectal examination in men, is also consistent with IC/BPS.

When IC/BPS is suspected, the main goal of the diagnostic evaluation is to exclude other conditions (see 'Differential diagnosis' below). Excluding malignancy is a main priority in the evaluation of patients with bladder pain. Our diagnostic approach is presented below (algorithm 1).

History — The clinician should elicit the characteristics of the pain or discomfort (eg, location, duration, relationship to bladder filling or emptying). Elements of the medical history related to the bladder should be elicited. A history of recurrent urinary tract infections, prior pelvic trauma, surgery, radiation, or neurologic disorder that might impact bladder function should prompt referral for specialized testing such as cystoscopy or urodynamics. Other symptoms that warrant workup for alternate diagnoses include hematuria, severe urinary incontinence, and generalized pelvic pain that is not worsened by bladder filling or relieved after urination. Evaluation of these conditions is discussed elsewhere. (See "Etiology and evaluation of hematuria in adults" and "Female urinary incontinence: Evaluation" and "Urinary incontinence in men" and "Chronic pelvic pain in adult females: Evaluation" and "Chronic prostatitis and chronic pelvic pain syndrome", section on 'Diagnostic approach'.)

For patients who report frequent voiding, we ask whether they are trying to avoid incontinence, which could suggest overactive bladder syndrome, or avoid discomfort, which would be more typical of IC/BPS. A voiding and fluid intake log is recommended to confirm the frequent, low-volume (<300 mL) voiding pattern that is characteristic of IC/BPS while also assessing for other possible symptoms such as abnormally high fluid intake or excessive nighttime urine production (form 1). (See 'Symptoms and signs' above.)

Validated symptom scales have been developed to assess IC/BPS symptom severity and to monitor clinical progress after diagnosis, but these are not helpful in distinguishing IC/BPS from other conditions and are typically used only by specialists for a focused visit regarding IC/BPS or for research. Two such scales are the IC Symptom and Problem Index and the Genitourinary Pain Index [38,39].

Physical examination — A focused physical examination of patients with IC/BPS is helpful in making a diagnosis by identifying typical pelvic tenderness, if present. It is also critical to excluding other conditions. Findings on examination that warrant workup for alternate diagnoses include significant pelvic prolapse, urethral diverticulum, inguinal hernia, uterine/cervical mass, prostate mass, and eroded/exposed vaginal mesh (algorithm 1). (See 'Differential diagnosis' below.)

Exquisite tenderness may make it impossible to perform an adequate digital rectal examination or, in women, an adequate pelvic examination. In this situation, for patients who have symptoms consistent with IC/BPS and no findings on history or urine testing concerning for alternate diagnoses, clinicians may choose to begin empiric treatment for IC/BPS. In such cases, full examination can be deferred until symptoms have improved enough to allow examination or if there is lack of response to treatment, in which case the presumptive diagnosis of IC/BPS should be questioned and examination should be done to evaluate for other etiologies.

Urine tests — Standard urine testing includes urinalysis and postvoid residual urine volume.

Urinalysis with microscopy should be performed in all patients with suspected IC/BPS to exclude infection and to evaluate for hematuria. For patients who have already had urine testing, repeated urinalysis is warranted if new signs or symptoms develop that suggest a superimposed urinary tract infection. A urine culture should be performed if urinalysis results suggest urinary tract infection. (See "Sampling and evaluation of voided urine in the diagnosis of urinary tract infection in adults".)

If hematuria is present, additional workup including cystoscopy is warranted to exclude urinary tract malignancy or other pathology. (See 'Differential diagnosis' below and 'Cystoscopy for selected patients' below and "Etiology and evaluation of hematuria in adults".)

A postvoid residual urine volume may be measured in all patients either by ultrasound or by using a catheter (usually avoided due to associated pain). Urinary retention could suggest bladder outlet obstruction or neurologic dysfunction as alternative causes of chronic bladder pain. (See "Urodynamic evaluation of women with incontinence", section on 'Postvoid residual volume'.)

Examination of the urine for sexually transmitted infections such as gonorrhea and chlamydia (which can cause dysuria) is reserved for patients at risk. (See "Clinical manifestations and diagnosis of Chlamydia trachomatis infections", section on 'Dysuria-pyuria syndrome due to urethritis' and "Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents", section on 'Urethritis'.)

Cystoscopy for selected patients — Cystoscopy is not required to make the diagnosis of IC/BPS. However, it may be performed to exclude other etiologies either on initial presentation or in patients who do not respond to treatment with oral medications (algorithm 1).

In some patients who do not respond to initial therapy, cystoscopic treatment of intravesical lesions with hydrodistention or fulguration may be beneficial. This is discussed elsewhere. (See "Interstitial cystitis/bladder pain syndrome: Management", section on 'Patients with refractory symptoms'.)

Excluding other etiologies — Cystoscopy is appropriate for many patients who have urologic abnormalities on history or examination, such as incontinence or elevated postvoid residual. In addition, patients with suspected IC/BPS who have hematuria on initial presentation or a history of bladder cancer even in the absence of other urologic abnormalities should undergo cystoscopy and other tests as needed to exclude urothelial malignancy. Bladder biopsy should be performed if there are findings suggestive of malignancy. There are few available data regarding the rate of urinary tract malignancy in patients with IC/BPS and hematuria, and the risk is likely similar to the general population (12.7 percent of patients with hematuria in a study from a hematuria clinic) [40-42]. (See 'Differential diagnosis' below and "Etiology and evaluation of hematuria in adults" and 'Cystoscopy for selected patients' above.)

In addition, in patients who have failed to respond to initial IC/BPS treatment, cystoscopic examination can be used to identify alternative causes of symptoms, such as an intravesical foreign body or structural lesion (eg, bladder stone, erosion of surgical mesh). (See 'Differential diagnosis' below.)

Identification of characteristic bladder lesions — IC/BPS is associated with several characteristic intravesical lesions, which may support the diagnosis, in the event that cystoscopy is performed to rule out other lesions or to evaluate patients who have not responded to treatment:

●Hunner lesions (reddened lesions on the bladder mucosa with attached fibrin deposits; typically bleed after hydrodistention)

●Increased numbers of mast cells on histologic examination of bladder biopsy specimens

To identify Hunner lesions, cystoscopy is performed with direct visualization before and after hydrodistention and biopsies are taken of suspected lesions.

Hunner lesions are identified in only 5 to 10 percent of patients; however, they are highly specific, and for those patients who have them, fulguration may help alleviate symptoms. (See "Interstitial cystitis/bladder pain syndrome: Management", section on 'Treatment of Hunner lesions'.)

Glomerulations (petechial red areas seen after hydrodistension) are also described in patients with IC/BPS but are of limited diagnostic value, since they are a nonspecific finding (eg, one study found glomerulations in 45 percent of healthy patients [43]), and their presence does not correlate well with symptoms [44].

Tests not routinely recommended

●Potassium sensitivity test – The potassium sensitivity test has been proposed by some researchers as useful for diagnosing IC/BPS [45] but is not recommended for routine use since its results are nonspecific for IC/BPS [46]. Furthermore, the test can be extremely painful to the patients, and there is no consistent evidence that the results provide additional information to guide treatment.

●Instillation of lidocaine – Instillation of lidocaine into the bladder has been described as an "anesthetic bladder challenge." With this test, improvement of symptoms after lidocaine instillation is considered suggestive of the presence of IC/BPS. However, as with the potassium sensitivity test, data are lacking to correlate these test results with treatment response.

●Urodynamic testing – Urodynamic testing has a limited role in the diagnosis of IC/BPS. There are no standard urodynamic criteria for the diagnosis of the condition, and the testing may cause significant patient discomfort. However, in certain patients in whom there is clinical uncertainty about the diagnosis, urodynamic testing can be helpful as part of the diagnostic process. As an example, urodynamic testing may help to guide therapy in patients with bladder pain symptoms who also have urinary incontinence or have evidence of poor bladder emptying.

DIAGNOSIS — We follow the American Urological Association guidelines, which use the following definition for the diagnosis of interstitial cystitis/bladder pain syndrome (IC/BPS): "An unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes" [4]. Pain associated with bladder filling and relieved by bladder emptying and pelvic tenderness on examination are characteristic features that further support the diagnosis when no other cause has been found.

The definition and diagnostic criteria for IC/BPS have varied over the past few decades. It is likely that refinement of terminology will continue to occur as the understanding of this condition increases.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of interstitial cystitis/bladder pain syndrome (IC/BPS) includes other conditions that result in chronic bladder pain and are described below.

●Bladder or urethral cancer – Bladder pain with or without hematuria is a common presentation of bladder cancer. Urethral cancer may also present with urethral or bladder pain with or without hematuria. In addition, hematuria may be a sign of malignancy in other parts of the urinary tract. The absence of a mass on physical examination does not reliably exclude urinary tract cancer. Thus, all patients undergoing evaluation for IC/BPS who have hematuria should undergo further evaluation. (See "Clinical presentation, diagnosis, and staging of bladder cancer" and "Urethral cancer" and "Etiology and evaluation of hematuria in adults".)

●Genital tract cancer – Genital tract cancers may also cause suprapubic/perivesical pain, as well as other urinary symptoms due to the presence of a pelvic mass and pressure on or invasion into the bladder. Appropriate evaluation should be performed for gynecologic or prostate cancers, depending upon physical examination findings and risk factors. (See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment" and "Vaginal cancer" and "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening" and "Clinical presentation and diagnosis of prostate cancer".)

●Infections – Urinary symptoms such as dysuria, frequency, or urgency may be the result of recurrent or persistent cystitis or urethritis (eg, due to chlamydia or gonorrhea in patients at risk of sexual transmitted infections). In these settings, urine testing, urine culture or urethral culture should be performed as appropriate. (See 'Urine tests' above.)

●Benign pelvic abnormalities – Benign pelvic masses may cause bladder discomfort and urinary symptoms. In women, uterine leiomyomas and pelvic organ prolapse are common conditions that may cause bladder pressure or pain.

●Intravesical pathology – Intravesical pathology may result in bladder pain or discomfort, such as a bladder stone or other foreign object. Risk factors for bladder stones include chronic bladder catheterization, ureteral stents, renal transplantation, and some medications (eg, fluoroquinolones) [47]. Patients with a history of pelvic surgery may have erosion of suture material or surgical mesh into the bladder wall. (See "Transvaginal synthetic mesh: Use in pelvic organ prolapse".)

●Urethral diverticulum – Diverticula can cause bladder pain or discomfort. Patients with this condition typically have postvoid dribbling of urine. (See "Urethral diverticulum in females".)

●Neurologic conditions – Patients with urinary retention due to bladder outlet obstruction or neurologic dysfunction may experience bladder pain. A postvoid residual is used to evaluate for urinary retention. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis" and 'Urine tests' above.)

●Chronic pelvic pain syndromes – Chronic pelvic pain syndromes occur in males and females. Symptoms in females include non-cyclic pain localized to the pelvis (may radiate out of the pelvis) of three to six months' duration or longer. Associated symptoms can include urinary or gastrointestinal symptoms, impaired quality of life, and mental health changes (eg, depression, anxiety). Chronic pelvic pain syndrome in males (also referred to as chronic prostatitis) is characterized by pain (in the perineum, lower abdomen, testicles, penis, and with ejaculation) and voiding difficulty (including bladder irritation and bladder outlet obstruction). A distinguishing characteristic of IC/BPS, whether it occurs in males or females, is that the pain is perceived to be located in the bladder, and it worsens with bladder filling and/or is relieved by urination. In patients with pelvic pain that is not impacted at all by bladder filling/emptying, the diagnosis of IC/BPS is less likely. (See "Chronic pelvic pain in adult females: Evaluation" and "Chronic prostatitis and chronic pelvic pain syndrome".)

INDICATIONS FOR REFERRAL TO A SPECIALIST — The initial diagnostic evaluation of most patients with interstitial cystitis/bladder pain syndrome (IC/BPS) may be performed by a primary care clinician. Certain patients with bladder pain symptoms warrant referral to a specialist, such as a urologist or urogynecologist, for additional diagnostic testing, including patients with the following symptoms or characteristics:

●Hematuria

●Complex symptoms (eg, pain and urinary incontinence)

●Incomplete bladder emptying

●A neurologic disorder that may affect bladder function

●Prior pelvic radiation, surgery or trauma

●Large uterine leiomyoma or other pelvic mass

●Prostate mass

●Pelvic organ prolapse beyond the vaginal opening

●No response to initial treatment with oral medications

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Bladder pain syndrome (interstitial cystitis) (The Basics)")

●Beyond the Basics topics (see "Patient education: Diagnosis of interstitial cystitis/bladder pain syndrome (Beyond the Basics)" and "Patient education: Treatment of interstitial cystitis/bladder pain syndrome (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks' duration, in the absence of infection or other identifiable causes. (See 'Diagnosis' above.)

●Clinical features – The characteristics of the bladder pain or discomfort in patients with IC/BPS are variable, but the most consistent feature is an increase in discomfort with bladder filling and a relief with voiding (table 1). (See 'Symptoms and signs' above.)

●Diagnostic evaluation – The main goal of the diagnostic evaluation is to exclude other conditions (algorithm 1). (See 'Differential diagnosis' above.)

●Physical examination – Common physical examination findings include widespread tenderness of the abdominal wall, hip girdle, buttocks, thighs, and pelvic floor, as well as tenderness of the bladder base and/or urethra. The main objective of the physical exam is to rule out other potential causes of symptoms that would warrant further evaluation, such as significant pelvic prolapse, urethral diverticulum, inguinal hernia, or uterine/cervical mass. (See 'Physical examination' above.)

●Urine tests – Urinalysis with microscopy should be performed in all patients to exclude significant hematuria and infection. Urine culture can be obtained if the urinalysis results are suspicious for infection. Patients should have measurement of postvoid residual urine volume. (See 'Urine tests' above.)

●Cystoscopy for selected patients – Cystoscopy is necessary to identify Hunner lesions, which can be treated and result in significant symptom relief. Cystoscopy is also important in patients with hematuria and other features to exclude underlying conditions. If performed, certain intravesical findings are consistent with IC/BPS. (See 'Cystoscopy for selected patients' above.)

●Indications for referral – Certain patients with bladder pain symptoms warrant referral to a specialist, such as a urologist or urogynecologist, for additional diagnostic testing. (See 'Indications for referral to a specialist' above.)