Most clinicians with outpatient practices see undiagnosed cases of IC/BPS. This chronic condition is characterized by pain perceived to be from the urinary bladder, urinary urgency and frequency, and nocturia. The majority of cases are diagnosed in women. Symptoms wax and wane for months or years or possibly even for the rest of the patient’s life. The spectrum of symptom intensity is broad. The pain can be excruciating, urgency can be distressing, frequency can be up to 60 times per 24 h, and nocturia can cause sleep deprivation. These symptoms can disrupt daily activities, work schedules, and personal relationships; patients with IC/BPS report less life satisfaction than do those with end-stage renal disease.
IC/BPS is not a new disease, having first been described in the late nineteenth century in a patient with the symptoms mentioned above and a single ulcer visible on cystoscopy (now called a Hunner’s lesion after the urologist who first reported it). Over the ensuing decades, it became clear that many patients with similar symptoms had no ulcer. It is now appreciated that only up to 10% of patients with IC/BPS have a Hunner’s lesion. The definition of IC/BPS, its diagnostic features, and even its name continue to evolve. The American Urological Association has defined IC/BPS 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.”
Many patients with IC/BPS also have other syndromes, such as fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and migraine. These syndromes collectively are known as functional somatic syndromes (FSSs): chronic conditions in which pain and fatigue are prominent features but laboratory tests and histologic findings are normal. Like IC/BPS, the FSSs often are associated with depression and anxiety. The majority of FSSs affect more women than men, and more than one FSS can affect a single patient. Because of its similar features and comorbidity, IC/BPS sometimes is considered an FSS.
Contemporary population studies of IC/BPS in the United States indicate a prevalence of 3–6% among women and 2–4% among men. For decades, it was thought that IC/BPS occurred mostly in women. These prevalence findings, however, have generated research aimed at determining the proportion of men who have symptoms usually diagnosed as chronic prostatitis (now known as chronic prostatitis/chronic pelvic pain syndrome) but who actually have IC/BPS.
Among women, the average age at onset of IC/BPS symptoms is the early forties, but the range is from childhood through the early sixties. Risk factors (antecedent features that distinguish cases from controls) primarily have been FSSs. Indeed, the odds of IC/BPS increase with the number of such syndromes present. Surgery was long thought to be a risk factor for IC/BPS, but analyses adjusting for FSSs refuted that association. About one-third of patients appear to have bacterial cystitis at the onset of IC/BPS.
The natural history of IC/BPS is not known. Although studies from urology and urogynecology practices have been interpreted as showing that IC/BPS lasts for the lifetime of the patient, population studies suggest that some individuals with IC/BPS do not consult specialists and may not seek medical care at all, and most prevalence studies do not show an upward trend with age—a pattern that would be expected with incident cases throughout adulthood followed by lifetime persistence of a nonfatal disease. It may be reasonable to conclude that patients in a urology practice represent those with the most severe and recalcitrant IC/BPS.
For the ≤10% of IC/BPS patients who have a Hunner’s lesion, the term interstitial cystitis may indeed describe the histopathologic picture. Most of these patients have substantive inflammation, mast cells, and granulation tissue. However, in the 90% of patients without such lesions, the bladder mucosa and interstitium are relatively normal, with scant inflammation.
Numerous hypotheses about the pathogenesis of IC/BPS have been put forward. It is not surprising that most early theories focused on the bladder. For instance, IC/BPS has been investigated as a chronic bladder infection. Sophisticated technologies have not identified a causative organism in urine or in bladder tissue; however, the patients studied by these methods had IC/BPS of long duration, and the results do not preclude the possibility that infection may trigger the syndrome or may be a feature of early IC/BPS. Other inflammatory factors, including a role for mast cells, have been postulated, but (as noted above) the 90% of patients without a Hunner’s ulcer have little bladder inflammation and do not have a prominence of mast cells in bladder tissue. Autoimmunity has been considered, but autoantibodies are low in titer, nonspecific, and thought to be a result rather than a cause of IC/BPS. Increased permeability of the bladder mucosa due to defective epithelium or glycosaminoglycan (the bladder’s mucous coating) has been studied frequently, but the findings have been inconclusive.
Investigations of causes outside the bladder have been prompted by the presence of comorbid FSSs. Many patients with FSSs have abnormal pain sensitivity as evidenced by (1) low pain thresholds in body areas unrelated to the diagnosed syndrome, (2) dysfunctional descending neurologic control of tactile signals, and (3) enhanced brain responses to touch in functional neuroimaging studies. Moreover, in patients with IC/BPS, body surfaces remote from the bladder are more sensitive to pain than is the case in individuals without IC/BPS. All these findings are consistent with upregulation of sensory processing in the brain. Indeed, a prevailing theory is that these concomitantly occurring syndromes have in common an abnormality of brain processing of sensory input. However, antecedence is a critical criterion for causality, and no study has demonstrated that abnormal pain sensitivity precedes either IC/BPS or the FSSs.
In some patients, IC/BPS has a gradual onset, and/or the cardinal symptoms of pain, urgency, frequency, and nocturia appear sequentially in no consistent order. Other patients can identify the exact date of onset of IC/BPS symptoms. More than half of the latter patients describe dysuria beginning on that date. As stated, only a minority of IC/BPS patients who obtain medical care soon after symptom onset have uropathogenic bacteria or leukocytes in the urine. These patients—and many others with new-onset IC/BPS—are treated with antibiotics for presumptive bacterial cystitis or, if male, chronic bacterial prostatitis. Persistent or recurring symptoms without bacteriuria eventually prompt a differential diagnosis, and IC/BPS is considered. Traditionally, the diagnosis of IC/BPS has been delayed for years, but recent interest in the disease has shortened this interval.
The pain of IC/BPS includes suprapubic prominence and changes with the voiding cycle. Two-thirds of women with IC/BPS report two or more sites of pain. The most common site (involved in 80% of women) and generally the one with the most severe pain is the suprapubic area. About 35% of female patients have pain in the urethra, 25% in other parts of the vulva, and 30% in nonurogenital areas, mostly the low back and also the anterior or posterior thighs or the buttocks. The pain of IC/BPS is most commonly described as aching, pressing, throbbing, tender, and/or piercing. What may distinguish IC/BPS from other pelvic pain is that, in 95% of patients, bladder filling exacerbates the pain and/or bladder emptying relieves it. Almost as many patients report a puzzling pattern in which certain dietary substances worsen the pain of IC/BPS. Smaller proportions—but still the majority—of patients report that their IC/BPS pain is worsened by menstruation, stress, tight clothing, exercise, and riding in a car as well as during or after vaginal intercourse.
The urethral and vulvar pains of IC/BPS merit special mention. In addition to the descriptive adjectives for IC/BPS mentioned above, these pains commonly are described as burning, stinging, and sharp and as being worsened by touch, tampons, and vaginal intercourse. Patients report that urethral pain increases during urination and generally lessens afterward. These characteristics have commonly resulted in diagnosis of the urethral pain of IC/BPS as chronic urethral syndrome and the vulvar pain as vulvodynia.
In many patients with IC/BPS, there is a link between pain and urinary urgency; that is, two-thirds of patients describe the urge to urinate as a desire to relieve their bladder pain. Only 20% report that the urge stems from a desire to prevent incontinence; indeed, very few patients with IC/BPS are incontinent. As mentioned above, urinary frequency can be severe, with ∼85% of patients voiding more than 10 times per 24 h and some as often as 60 times. Voiding continues through the night, and nocturia is common, frequent, and often associated with sleep deprivation.
Beyond these common symptoms of IC/BPS, additional urinary and other symptoms may be present. Among the urinary symptoms are difficulty in starting urine flow, perceptions of difficulty in emptying the bladder, and bladder spasms. Other symptoms include the manifestations of comorbid FSSs as well as symptoms that do not constitute recognized syndromes, such as numbness, muscle spasms, dizziness, ringing in the ears, and blurred vision.
The pain, urgency, and frequency of IC/BPS can be debilitating. Proximity to a bathroom is a continual focus, and patients report difficulties in the workplace, leisure activities, travel, and simply leaving home. Familial and sexual relationships can be strained.
Traditionally, IC/BPS has been considered a rare condition that is diagnosed by urologists at cystoscopy. However, this disorder is much more common than once was thought; it is now being considered earlier in its course and is being diagnosed and managed more often by primary care clinicians. Results of physical examination, urinalysis, and urologic procedures are insensitive and/or nonspecific. Thus, diagnosis is based on the presence of appropriate symptoms and the exclusion of diseases with a similar presentation.
Three categories of disorders can be considered in the differential diagnosis of IC/BPS. The first comprises diseases that manifest as bladder pain (see above) or urinary symptoms. Among the latter diseases is overactive bladder, a chronic condition of women and men that presents as urgency and frequency and that can be distinguished from IC/BPS by the patient’s history: pain is not a feature of overactive bladder, and its urgency arises from the need to avoid incontinence. Endometriosis is a special case: it can be asymptomatic or can cause pelvic pain, dysmenorrhea, and dyspareunia—i.e., types of pain that mimic IC/BPS. Endometrial implants on the bladder (although uncommon) can cause urinary symptoms, and the resulting syndrome can mimic IC/BPS. Even if endometriosis is identified, it is difficult in the absence of bladder implants to determine whether it is causative of or incidental to the symptoms of IC/BPS in a specific woman.
The second category of disorders encompasses the FSSs that can accompany IC/BPS. IC/BPS can be misdiagnosed as gynecologic chronic pelvic pain, irritable bowel syndrome, or fibromyalgia. The correct diagnosis may be entertained only when either changes of pain with altered bladder volume or urinary symptoms become more prominent.
The third category involves syndromes that IC/BPS mimics by way of its referred pain, such as vulvodynia and chronic urethral syndrome. Therefore, IC/BPS should be considered in the differential diagnosis of persistent or recurrent “urinary tract infection” (UTI) with sterile urine cultures; overactive bladder with pain; chronic pelvic pain, endometriosis, vulvodynia, or FSSs with urinary symptoms; and “chronic prostatitis.” As mentioned above, important clues to the diagnosis of IC/BPS are pain that changes with bladder volume or with certain foods or drinks. Common among these are chilies, chocolate, citrus fruits, tomatoes, alcohol, caffeinated drinks, and carbonated beverages; full lists of common trigger foods are available at the websites cited in the treatment section below.
Cystoscopy under anesthesia formerly was thought to be necessary for the diagnosis of IC/BPS because of its capacity to reveal a Hunner’s lesion or—in the 90% of patients without an ulcer—petechial hemorrhages after bladder distention. However, because Hunner’s lesions are uncommon in IC/BPS and petechiae are nonspecific, cystoscopy is no longer necessary for diagnosis. Accordingly, the indications for urologic referral have evolved toward the need to rule out other diseases or to administer more advanced treatment.
A typical patient presents to the primary clinician after days, weeks, or months of pain, urgency, frequency, and/or nocturia. The presence of urinary nitrites, leukocytes, or uropathogenic bacteria should prompt treatment for UTI in women and chronic bacterial prostatitis in men. Persistence or recurrence of symptoms in the absence of bacteriuria should prompt a pelvic examination for women, an assay for serum prostate-specific antigen for men, and urine cytology and inclusion of IC/BPS in the differential diagnosis for both sexes.
In the diagnosis of IC/BPS, inquiries about pain, pressure, and discomfort are useful; IC/BPS should be considered if any of these sensations are noted in one or more anterior or posterior sites between the umbilicus and the upper thighs. Nondirective questions about the effect of bladder volume changes include “As your next urination approaches, does this pain get better, get worse, or stay the same?” and “After you urinate, does this pain get better, get worse, or stay the same?” Establishing that the pain is exacerbated by the consumption of certain foods and drinks not only supports the diagnosis of IC/BPS but also serves as the basis for one of the first steps in managing this syndrome. A nondirective way to ask about urgency is to describe it to the patient as a compelling urge to urinate that is difficult to postpone; follow-up questions can determine whether this urge is intended to relieve pain or prevent incontinence. To assess severity and provide quantitative baseline measures, pain and urgency should be estimated by the patient on a scale of 0–10, with 0 being none and 10 the worst imaginable. Frequency per 24-h period should be determined and nocturia assessed as the number of times per night the patient is awakened by the need to urinate.
About half of patients with IC/BPS have intermittent or persistent microscopic hematuria; this manifestation and the need to exclude bladder stones or cancer require urologic or urogynecologic referral. Initiation of therapy for IC/BPS does not hamper subsequent urologic evaluation.
TREATMENT Interstitial Cystitis/Bladder Pain Syndrome
The goal of therapy is to relieve the symptoms of IC/BPS; the challenge lies in the fact that no treatment is uniformly successful. However, most patients eventually obtain relief, generally with a multifaceted approach. The American Urological Association’s guidelines for management of IC/BPS are an excellent resource. The correct strategy is to begin with conservative therapies and proceed to riskier measures only if necessary and under the supervision of a urologist or urogynecologist. Conservative tactics include education, stress reduction, dietary changes, medications, pelvic-floor physical therapy, and treatment of associated FSSs.
Months or even years may have passed since the onset of symptoms, and the patient’s life may have been disrupted continually, with repeated medical visits provoking frustration and dismay in both patient and physician. In this circumstance, simply giving a name to the syndrome is beneficial. The physician should discuss the disease, the diagnostic and therapeutic strategies, and the prognosis with the patient and with the spouse and/or other pertinent family members, who may need to be made aware that although IC/BPS has no visible manifestations, the patient is undergoing substantial pain and suffering. This information is particularly important for sexual partners, as exacerbation of pain during and after intercourse is a common feature of IC/BPS. Because stress can worsen IC/BPS symptoms, stress reduction and active measures such as yoga or meditation exercises may be suggested. The Interstitial Cystitis Association (http://www.ichelp.com) and the Interstitial Cystitis Network (http://www.ic-network.com) can be useful in this educational process.
In constructing a benign diet, some of the many patients who identify particular foods and drinks that exacerbate their symptoms find it useful to exclude all possible offenders and add items back into the diet one at a time to confirm which ones worsen their symptoms. Patients also should experiment with fluid volumes; some find relief with less fluid, others with more.
The pelvic floor is often tender in IC/BPS patients. Two randomized controlled trials showed that weekly physical therapy directed at relaxation of the pelvic muscles yielded significantly more relief than a similar schedule of general body massage. This intervention can be initiated under the direction of a knowledgeable physical therapist who recognizes that the objective is to relax the pelvic floor, not to strengthen it.
Among oral medications, nonsteroidal anti-inflammatory drugs are commonly used but are controversial and often unsuccessful. Two randomized controlled trials showed that amitriptyline can diminish IC/BPS symptoms if an adequate dose (≥50 mg per night) can be given. This drug is used not for its antidepressant activity but because of its proven effects on neuropathic pain; however, it is not approved by the U.S. Food and Drug Administration for treatment of IC/BPS. An initial dose of 10 mg at bedtime is increased weekly up to 75 mg (or less if a lower dose adequately relieves symptoms). Side effects can be expected and include dry mouth, weight gain, sedation, and constipation. If this regimen does not control symptoms adequately, pentosan polysulfate, a semisynthetic polysaccharide, can be added at a dose of 100 mg three times a day. Its theoretical effect is to replenish a possibly defective glycosaminoglycan layer over the bladder mucosa; randomized controlled trials suggest only a modest benefit over placebo. Adverse reactions are uncommon and include gastrointestinal symptoms, headache, and alopecia. Pentosan polysulfate has weak anticoagulant effects and perhaps should be avoided by patients with coagulation abnormalities.
Anecdotal reports suggest that successful therapy for one FSS is accompanied by diminished symptoms of other FSSs. As has been noted here, IC/BPS often is associated with one or several FSSs. Thus, it seems reasonable to hope that, to the extent that accompanying FSSs are treated successfully, the symptoms of IC/BPS will be relieved as well.
If several months of these therapies in combination do not relieve symptoms adequately, the patient should be referred to a urologist or urogynecologist who has access to additional modalities. Cystoscopy under anesthesia allows distention of the bladder with water, a procedure that provides ∼40% of patients with several months of relief and can be repeated. For those few patients with a Hunner’s lesion, fulguration may offer relief. Bladder instillation of solutions containing lidocaine or dimethyl sulfoxide can be administered. Physicians experienced in the care of IC/BPS patients have used anticonvulsants, narcotics, and cyclosporine as components of therapy. Pain specialists can be of assistance. Sacral neuromodulation with a temporary percutaneous electrode can be tested and, if effective, can then be performed with an implanted device. In a very small number of patients with recalcitrant symptoms, surgeries, including cystoplasty, partial or total cystectomy, and urinary diversion, may provide relief.