Chapter 159 Cystitis and Interstitial Cystitis/Painful Bladder Syndrome
Bladder infections in women are surprisingly common: 10% to 20% of all women have urinary tract discomfort at least once a year, 37.5% of women with no history of urinary tract infection (UTI) will have such an infection within 10 years, and 2% to 4% of apparently healthy women have elevated levels of bacteria in their urine, indicative of an unrecognized UTI. Women with a history of recurrent UTI will typically have an episode at least once every year.1 Recurrent bladder infections can be a significant problem because 55% will eventually involve the upper urinary tract (i.e., the kidneys). Recurrent kidney infections can cause abscess formation, disseminated intravascular coagulation, acute respiratory distress syndrome, sepsis, and chronic progressive renal damage, resulting in scarring and, for some, kidney failure.
Except in infants, UTIs are much less common in males than females and in general indicate an anatomic abnormality, a prostate infection, or rectal intercourse. Table 159-1 lists incidence by age and gender.
|Age Group||Incidence||Male:Female Ratio|
Modified from Rubin RH. Infections of the urinary tract. In Dale DC, Federman DD, eds. Scientific American Medicine. New York: Scientific American, 1997.
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder disorder characterized by chronic pelvic pain (CPP) and irritative voiding symptoms. IC/PBS is not due to infection; it is characterized by symptoms similar to cystitis, and patients may also report otherwise undiagnosed CPP. The symptoms of IC/PBS can overlap with such conditions as endometriosis, recurrent UTI, CPP, overactive bladder, and vulvodynia. Studies have indicated that IC affects 52 to 67 per 100,000 people in the United States.2 Some investigators believe these numbers are vastly underestimated owing to lack of proper diagnosis.
The diagnosis of bladder infection is imprecise because clinical symptoms and the presence of significant amounts of bacteria in the urine do not correlate well. As indicated in Table 159-2, only 60% of women with the typical symptoms of UTI actually have significant levels of bacteria in their urine. Equally important, however, is the fact that 20% have the more potentially serious involvement of the upper tract.
|Diagnosis||Percentage of Subjects|
|Upper urinary tract infection||20|
|Low levels of bacteria in urethra||16|
|Other (e.g., herpes, gonorrhea, pelvic inflammatory disease)||12|
Modified from Reilly BM. Practical strategies in outpatient medicine. Philadelphia: Saunders, 1984:277.
In general, the diagnosis is made according to signs and symptoms and urinary findings. A pelvic examination is indicated if there is a history consistent with vaginitis or cervicitis or if there is confusion regarding diagnosis. Microscopic examination of the infected urine shows high levels of white blood cells (WBCs) and bacteria. Culturing the urine determines the quantity and type of bacteria involved. As shown in Table 159-3, Escherichia coli (from the colon) is by far the most common. The presence of fever, chills, and low back pain can indicate involvement of the kidneys. Those with recurrent infections should be examined by intravenous urogram to determine if a structural abnormality is present.3
Modified from Rubin RH. Infections of the urinary tract. In Dale DC, Federman DD, eds. Scientific American Medicine. New York: Scientific American, 1997.
IC/PBS can also be difficult to diagnose because the symptoms overlap with a variety of other disorders, including endometriosis, UTI, chronic CPP, overactive bladder (OAB), and vulvodynia.4,5 Because there is no definitive diagnostic test, IC/PBS remains a diagnosis of exclusion. The presence of additional symptoms caused by other pain generators can confuse the diagnosis even further. Patients may not receive an accurate diagnosis for years. The median time between the development of IC/PBS symptoms and the diagnosis is approximately 5 years.6
CPP is pain lasting 6 months or longer that is severe enough to affect daily functioning or requires medical care.4 The specific etiology of CPP is often unknown and may be multifactorial.7 Gynecologic conditions that can cause CPP include endometriosis, adhesions, pelvic inflammatory disease (PID), cysts, and polyps.7 However, a retrospective cohort analysis of a large primary care database in the United Kingdom found that only 20.2% of all cases of CPP had a gynecologic etiology.8 Gastrointestinal diagnoses represented 37.7% of cases, with irritable bowel syndrome (IBS) accounting for 29.1%. Cystitis accounted for 30.8% of diagnoses in this population of women with noncyclic pain lasting for 6 months or longer. Up to one half of the women in primary care practices who have CPP may have more than one diagnosis for their pain. As described previously, it is common for a patient with CPP to have both endometriosis and IC/PBS.7
Physical examination is a critical component of diagnosing IC/PBS. In IC/PBS patients, this can be emotionally distressing because of pain, so it is important that the physician proceed slowly and carefully.9 Because the bladder is a pain generator in IC/PBS, tenderness with single-digit examination of the trigonal area (bladder base or urethra) can help establish a diagnosis of IC/PBS, as can pain in the pelvic floor or levator ani.4 Patients with IC/PBS tend to have urethral or bladder tenderness, whereas those with vestibulodynia have vestibular tenderness.10 Tenderness on single-digit examination of the vaginal fornices can help distinguish endometriosis from IC/PBS.9
Urinalysis can rule out hematuria, and urine culture is required to identify bladder infection.9 Cytology and computed tomography with double contrast when indicated (hematuria, history of smoking, 40 years of age and older) can help rule out urinary tract malignancies.11 Patients with results suggesting a malignancy should be referred to a urologist. Several optional diagnostic tests can help diagnose IC/PBS. The presence of glomerulations seen on cystoscopy with hydrodistention may aid in the diagnosis of IC/PBS. A negative cystoscopic evaluation should never be used to rule out IC/PBS, because many patients with early IC/PBS will not have glomerulations.12 The potassium sensitivity test (PST) may indicate a defective bladder lining. The PST involves intravesical instillation of a potassium solution, which triggers symptoms of pain and urgency in patients with abnormal permeability of the bladder surface.13 Intravesical instillation of an anesthetic cocktail can be used as a diagnostic tool as well as a treatment. Known as the “anesthetic bladder challenge,” this test can help localize pain to the bladder.14,15
The optimal clinical method for obtaining a urine sample is the voided midstream specimen. It involves cleaning of the urethral meatus or vaginal vestibule before the sample is collected. If vaginal epithelial cells are present, a new specimen should be collected. To avoid repeating the collection, a satisfactory technique for the female, called “the clean catch,” consists of spreading the labia and cleaning the area with two gauze sponges moistened with an antimicrobial solution and a dry gauze sponge. The washing is accomplished by making a single front-to-back motion with each of the two moist sponges and then the dry sponge. While the labia are still held apart, a small amount of urine is allowed to pass into the toilet (or bedpan); then a midstream specimen is collected in a sterile container and immediately closed.
Occasionally, the urine must be collected via catheterization. This is a more invasive procedure and carries with it a 1% to 2% chance of initiating a UTI via the introduction of microorganisms into the bladder. Suprapubic aspiration is the most accurate method of urine collection, but obviously it is also the most invasive one.
Several methods are routinely employed in the detection of bacteria in the urine. They range from the use of dipsticks to microscopic examination and culture. For most accurate determinations, the urine should be examined within 1 hour. If examination must be delayed, refrigeration at 58° C preserves the urine for most routine examinations. However, culturing requires that the urine not be refrigerated for more than 8 hours.
The modern examination of urine specimens typically involves the use of reagent strips, which are dipped into the urine and removed. Parts of each dipstick are impregnated with chemicals that react with specific substances in the urine to produce various colors. Color standards, with which the color can be compared, are provided. Careful attention must be paid to match the dipstick to the color standard at the appropriate time. Instructions accompany commercially prepared dipsticks.
Dipsticks are invaluable for qualitative and rough quantitative analysis. Typically they provide information on pH, protein, glucose, ketones, bilirubin, hemoglobin, leukocyte esterase, nitrite, and urobilinogen. Some dipsticks also allow for the detection of WBCs and bacteria (including semiquantitative cultures).
Urinary infections typically increase the number of WBCs present. The leukocyte esterase test is used to detect WBCs in the urine. Because many common organisms contain enzymes that reduce nitrate in the urine to nitrite (Box 159-1), the measurement of urinary nitrite provides an inexpensive and rapid way to detect significant bacteriuria, but the findings should be confirmed by culture. Although both tests have a high specificity (approximately 95%), the leukocyte esterase test is approximately 80% to 90% sensitive, whereas the nitrite test is only approximately 50% sensitive compared with a quantitative culture as the gold standard. However, the combination of both tests improves the sensitivity up to the range of 85% to 90%.16
BOX 159-1 Nitrates and Biological Organisms
Microscopic examination should be performed within the first hour after collection. A drop of fresh urine or a drop of resuspended sediment from centrifuged fresh urine is placed on a microscope slide, covered with a coverslip, and examined with the high-dry objective under reduced illumination. The presence of more than 10 bacteria per field in an unstained specimen suggests a bacterial count of more than 100,000/mL of urine. Smears may also be made using a Gram stain and examined under the oil immersion objective. The presence of WBCs further indicates an infectious process. The presence of large quantities of protein, WBC casts, or both in the micrographic examination may be indicative of renal involvement, most commonly pyelonephritis.
Typically, only quantitative cultures are used. After introduction of diluted urine to the suitable medium and incubation, the colonies are counted and multiplied by the dilution factor to yield the bacterial count per milliliter. Bacteriuria is considered significant if it is more than 100,000/mL, but even 1000/mL is considered clinically significant in the presence of symptoms characteristic of UTI. Most physicians are now employing semiquantitative tests17 using dipsticks or glass slides coated with culture media. Colonies are counted and appearance is compared within 12 to 24 hours of incubation. For recurrent or chronic infection, sensitivity studies are often performed.
In more than 95% of UTIs, a single bacterial species is the problem. When mixed bacterial species are grown, the probability of contamination is high. Recurrence of UTI after the initial bacterial infection is resolved is common.
Staphylococcus epidermidis, diphtheroids, and lactobacilli are commonly found in the distal urethra but rarely cause UTI. Symptoms of recurrent UTI include urgency, frequency, nocturia, and pelvic pain. Diagnosis is established by a positive urine culture.18
A detailed medical history and physical examination are the basis for diagnosing the cause of CPP. The use of questionnaires, such as the Pelvic Pain, Urgency Frequency Questionnaire (PUF), or O’Leary Sant Questionnaire (OLS) indices, may elicit information about urinary symptoms. Tenderness of the bladder base on pelvic examination is a characteristic feature of IC/PBS that may help to distinguish it from other causes of CPP.9 Optional tests, including laparoscopy and diagnostic imaging, may also be helpful.6 Additional useful information may be gained from the PST or intravesical anesthetic challenge.
Endometriosis is characterized by the presence of endometrial-like glands and stroma outside the uterine cavity. Symptoms include pain in the lower abdomen, dysmenorrhea, and dyspareunia and can also include such voiding symptoms as dysuria and frequency.20 Endometriosis and IC/PBS frequently coexist in the same patient. In one study of women with CPP and bladder tenderness on examination, more than 70% had both endometriosis and IC/PBS.21
OAB is characterized by urgency with or without urge incontinence and usually includes frequency and nocturia. The key symptom is urgency.22 OAB and IC/PBS can coexist in the same patient. Urgency can be caused by detrusor overactivity, which usually can be demonstrated through urodynamic testing. Urgency is a common symptom of both OAB and IC/PBS, although the cause differs. In patients with OAB, urgency results in a strong desire to avoid leakage, whereas in patients with IC/PBS, urgency results in a strong need to void to relieve pain caused by bladder fullness.23
Vulvodynia is characterized by vulvar discomfort, often reported as burning pain. Pain can occur during intercourse, during vigorous activity, after intercourse, or even at rest. The etiology of vulvodynia is unknown, and the diagnosis is one of exclusion. Symptoms of vulvodynia that overlap those of IC/PBS include pain and dyspareunia but not frequency or nocturia; this can help to distinguish vulvodynia from IC/PBS. It is also possible for a patient to have both IC/PBS and vulvodynia. The history and physical examination are important in diagnosing vulvodynia. A history of chronic pain at the vestibule lasting more than 3 months can suggest vulvodynia. Infectious causes may include viral, bacterial, or fungal organisms; therefore, these must be ruled out as causes of vulvar pain. Vulvar dermatoses may also account for vulvar symptoms.24 Tenderness to pressure with a cotton swab at the vestibule is a hallmark of vulvodynia,25 whereas tenderness at the bladder base is typical of IC/PBS.
The primary goal in the natural approach to treating infectious cystitis is enhancing normal host protective measures against UTI. Specifically, this means enhancing the flow of urine by achieving and maintaining proper hydration, promoting a pH that inhibits the growth of the organisms, preventing bacterial adherence to the endothelial cells of the bladder, and enhancing the immune system. In addition, several botanical medicines with antimicrobial activity can be employed.
Increased urine flow can easily be achieved by increasing the quantity of liquids consumed. Ideally, these liquids should be in the forms of pure water and herbal teas. Fresh fruit and vegetable juices should be diluted with at least twice the amount of water. The patient should be encouraged to drink at least 2 L of liquid, with at least half being simply pure water. The patient should also be advised to avoid such liquids as soft drinks, concentrated fruit drinks, coffee, and alcoholic beverages.
In addition to the general measures given later for cystitis, the focus for interstitial cystitis is on enhancing the integrity of the interstitium along with the lining of the bladder wall. The “leaky bladder urothelium” theory postulates that there is a problem with the glycosaminoglycan layer of the bladder epithelium, which results in making the bladder wall more permeable to potassium, causing inflammation and pain. The elimination of food allergies to reduce inflammation appears to be a valid goal even though the association between food allergies and cystitis is not well established. Food allergies have been shown to produce cystitis in some patients. Repeated ingestion of a food allergen could easily explain the chronic nature of interstitial cystitis. For a complete discussion of food allergies, see Chapter 15.
Education of patients with IC/PBS helps empower them to control their symptoms and to be active participants in their own therapy. Patients should be counseled to avoid triggers that lead to increased IC/PBS symptoms. They should also be encouraged to reduce stress and use support groups to deal with the impact IC/PBS has on their daily lives. Dietary changes can provide relief of symptoms.26
Herati et al27 established the prevalence and characteristics of food sensitivities in patients with IC/PBS and Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS). Validated questionnaires containing a list of 175 comestibles as well as pain questions were mailed to 325 patients with IC/PBS and 286 with CP/CPPS. The researchers found that although patients with IC/PBS were more likely to be food sensitive than patients with CP/CPPS, these questionnaires showed that the symptoms of patients with both IC/PBS and CP/CPPS were aggravated by similar comestibles, such as grapefruit juice, spicy foods, alcohol, and caffeinated coffee. The findings also revealed that the symptoms of both groups of patients were improved by certain comestibles, namely water and an antacid containing calcium glycerophosphate (Prelief).27 In 2007, a study done at Long Island University reported that over 90% of patients with interstitial cystitis experience an increase in symptoms when they consume certain foods and beverages, especially coffee, tea, soda, alcoholic beverages, citrus fruits and juices, artificial sweeteners, and hot pepper.28
Food restrictions have not been conclusively proved to help slow the progression of the disease or to improve its course. Usually food restriction should be weighed against the decrease in the patient’s quality of life. After 2 weeks, patients are usually asked to start adding one food item back into their diets every 3 days to identify any specific alimentary sensitivity.
Medical treatments include tricyclic antidepressants (amitriptyline being the most popular),29 anticholinergics to reduce symptoms of urinary urgency, and antihistamines for their efficacy in decreasing mast cell activation and reducing inflammation.30,31
Mast cells, once thought to be responsible for allergic reactions, have in some studies been shown to be critically important in interstitial cystitis. Current evidence from clinical and laboratory studies confirms that they play a central role in IC/PBS.32 Histamine causes pain, swelling, and scarring and prevents the lining of the bladder from healing.
Pentosan polysulfate sodium (Elmiron), is an FDA-approved oral treatment heparinoid compound that is thought to replenish the defective bladder lining. According to one placebo-controlled randomized clinical trial, when it is taken orally, only 1% to 3% of the active drug reaches the bladder. Based on levels of improvement and side effects, treatment can be continued for 3 months and then extended as needed.33
Second-line therapies include immunosuppressive agents like prednisone, which was used to treat severe IC/PBS in one small clinical trial.34 Thirty patients with the Hunner’s ulcer subtype of IC/PBS showed considerable improvement following endoscopic submucosal injection of triamcinolone.35 Cyclosporine has been shown in clinical trials to relieve the symptoms of severe IC/PBS.36 Symptoms generally recur after treatment is discontinued.
Intravesical therapy can be used for flare management. Dimethylsulfoxide (DMSO) is the only FDA-approved intravesical IC/PBS treatment.37 Intravesical instillation of anesthetic can bring immediate relief. A study of patients with IC/PBS receiving intravesical instillation of heparin and alkalinized lidocaine showed that this treatment provided immediate and sustained relief of pain and urgency.38
Muscle relaxants, used to treat increased muscle spasticity of the pelvic floor associated with CPP, appear to have a beneficial effect. Cyclobenzaprine is an agent closely related to the tricyclic antidepressants. It is used at starting doses of 10 mg daily, which can be prescribed up to three times daily. Tizanidine is a centrally acting alpha2 agonist shown to be superior to placebo in treating spasticity in several conditions. In addition, clonazepam has been useful in treating neuropathic pain.40