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Interstitial cystitis: When urgency and frequency mean more than routine inflammation

Abstract: Although it's not a malignant or infectious condition, interstitial cystitis can be as disabling and sometimes even more difficult to manage. Many women undergo ineffective gynecologic surgery, and some men have inappropriate transurethral prostatectomy in a desperate attempt to subdue their pain. The authors provide tips for primary care physicians on making a presumptive diagnosis and suggest symptomatic relief methods to try before referral.

Interstitial cystitis is a common but poorly understood syndrome that affects tens of thousands of women and perhaps a few thousand men. Neither cause nor cure is known. It has also been called painful bladder syndrome. because of the nature of its symptoms. Classically, patients complain of bladder pain, urgency, frequency, noctura, and dysuria. Voiding often produces only small volumes. Bladder emptying may provide some short-term relief from symptoms, but patients are often miserable and some are depressed. Interstitial cystitits definitely decreases the quality of life.

The condition was first described by Hunner¹ in 1915 in several women who had the symptoms mentioned and ulcerations or linear cracks in the bladder mucosa seen cystoscopically. Now called Hunner's ulcer, the ulceration is a classic sign and immediately diagnostic of interstitial cystitis. however, it is usually not present at the time of cystoscopy. More often, diagnosis is made by exclusion of other conditions that may cause this group of symptoms.

Possible Causes

ALthough much research is being conducted in attempts to better understand interstitial cystitis, its cause remains a mystery. At present, no specific factor or agent, including infection and tumor, has been implicated as the cause. In fact there may be more than one cause.

Normally, the mucosa of the bladder has a protective lining made up mostly of glycosaminoglycans. Parsons and colleagues² and others^3,4 have postulated that a defect in the glycosaminoglycan layer leads to absorption of potentially toxic substances by the bladder wall, initiating a chronic inflammatory reaction. Other working theories include mast cell abnormalities⁵, immunologic abnormalities⁶, and other causes, which are reviewed by Pontari and Hanno.⁷

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Patient characteristics

Overwhelmingly , interstitial cystitis affects women. Less than 5% of our patients with documented interstitial cystitis have been men. The literature reports the female-to-male ratio to be about 9:1. Most patients are white⁸. The age range is considerable. Held and associates⁹ found the median patient age at symptom onset to be between 40 and 50 years. In our experience, symptom onset is most often in the second or third decade of life. Onset may be a little later in men, but there is wide variation in both sexes. Although exceedingly rare, interstitial cystitis in children has been reported.

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Risk factors

Some risk factors for interstitial cystitis have been suggested, but the possible link between these factors and the disease is not clear. Koziol⁸ found the following to be present in statistically significant numbers in patients with interstitial cystitis: hysterectomy, medication allergies, irritable bowel syndrome, paresthesias, abdominal complaints, sinusitis, frequent upper respiratory tract infections, and arthritis.

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Diagnosis

To most urologists, interstitial cystitis appears to be a very common condition that is often underdiagnosed or improperly diagnosed. The number of people affected is somewhat controversial. One estimate is about 18 cases/100,000 population worldwide⁷. An awareness of the disease and its symptoms is essential in making the diagnosis.

As mentioned, the classic definition of interstitial cystitis is the presence of Hunner's ulcers on cystoscopic examination of the bladder, but this feature is found only infrequently. Submucosal petechiae are also a diagnostic cystoscopic finding. Characteristic histologic findings are mast cells and fibrosis in the deep layers of the bladder wall.

However, before referring patients for cystoscopy, primary care physicians may be able to make a presumptive diagnosis by looking for appropriate clinical criteria. In workshos held in 1987 and 1988, the National Institute of Diabetes and Digestive and Kidney Diseases developed inclusion and exclusion criteria for patients being considered for its studies of interstitial cystitis, and these criteria (table 1) may be used in diagnosis. Inclusion criteria are bladder pain, urinary urgency and frequency, and a bladder capacity of less than 350 mL. The absence of any of these factors, absence of nocturia, and symptom duration of less than 9 months are among the excluding factors.

Before the diagnosis of interstitial cystitis is presumed, several conditions need to be ruled out. Bladder or prostate infection and bladder cancer are common conditions that may mimic interstitial cystitis. Other types of cystitis such as radiation, tuberculous, and chemical cystitis (e.g., after chemotherapy with cyclophosphamide[Cytoxan, Neosar]), must be considered and can often be eliminated through history taking alone.

Primary care physicians may find the following tips helpful in further identifying interstitial cystitis and eliminating other disorders.

Pelvic examination in women often reveals tenderness of the bladder base
Findings of urinalysis may be entirely normal or show microscopic hematuria or pyuria. Urine culture is usually sterile. (Of course, a patient with interstitial cystitis may also have a bladder infection.)
Urine cytoogy may be helpful in ruling out a malignant bladder tumor.

No other laboratory or imaging studies aid in diagnosis. After these evaluations are completed, confirmation of the diagnosis depends on a urologist's cystoscopic findings. Hydrodistention of the bladder is often performed during cystoscopy, using general anesthesia. Hydrodistention of the bladder is often performed during cystoscopy, using general anesthesia. Hydrodistention consists of filling the bladder with saline solution or sterile water beyond its normal capacity. Pinpoint hemorrhages or fissures with bleeding may appear on distention. Although hydrodistention of the bladder is used in diagnosis of itnerstitial cystitis, it also provides symptomatic relief to some patients, for reasons that are not understood.

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Patient criteria for NIDDK study of interstitial cystitis

Inclusion Data

Pinpoint bleeding or Hunner's ulcers on cystoscopy
Bladder pain or urinary urgency

Exclusion criteria (any of the following)

Bladder capacity of more than 350 mL on cystometrogram (using gas or water) performed with patient awake
No intense urge to void when bladder is filled to 100 mL of gas or 150 mL of water at medium fill rate (30 to 100 mL/min)
Involuntary bladder contractions on cystometrogram at medium fill rate
Symptom duration less than 9 months
Absence of nocturia
Symptoms relieved by antimicrobial, antiseptic, anticholinergic, or antispasmodic agents
Urination frequency less than eight times during the day
Diagnosis of bacterial cystitis or prostitis within 3 months
Bladder or lower ureteral calculi
Active genital herpes
Uterine, cervical, vaginal, or urethral cancer
Urethral diverticulum
Radiation, tuberculous, or chemical cystitis (e.g., after use of cyclophosphamide [Cytoxan, Neosar])
Vaginitis
Benign or malignant bladder tumor
Age under 18

NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases
Adapted from Interstitial Cystitis, Bethesda: National Institute of Diabetes and
Digestive and Kidney Diseases (NIH publication No. 94-3220).

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Coping tips for patients with interstitial cystitis

Emotional support is very important in coping with ongoing pain. Such support can often be supplied by family and friends, but others who have the same disorder may be especially helpful. The Interstitial Cystitis Assocation of America can provide information and the location of the support group nearest you. Write the association at PO Box 1553, Madison Square Station, New York, NY 10159-1553 or call 212.979.6057 or 800.ICA.1626

Here are some tips to remember:

Find a healthcare team that is sympathetic and helpful.
Understand that you healthcare team does not know all the answers and may be as frustrated as you are.
Stay in touch with family and friends. Don't become isolated.
Involve your family in treatment decisions.
Remember that interstitial cystitis is only one part of your life. Don't allow it to become the focus.
Talk to others about their experiences and ways of coping.

When a patient is seen for the first time and appears to hav einterstitial cystitis, a trial of analgesics, anticholinergic agents, and smooth-muscle relaxants (e.g., oxybutynin chloride [Ditropan], 5 mg twice a day) is a good way to attempt symptom relief while awaiting urologic consultation. A problem with oral medications is that they are excreted in small amounts in the urine, either unchanged or as inactive metabolites. Side effects are common because of the high doses or prolonged courses of treatment (up to 6 months) needed to achieve therapeutic benefit¹⁰.

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Treatment methods.

Many methods have been tried to provide relief from symptoms of interstitial cystitis. However, no standard or universally accepted treatment has been found that reliably resolves this debilitating medical problem. Hunner¹ claimed that surgical removal of the ulcers was effective in a few of his patients early in the century, but today this method is used only in rare instances.

Oral Therapy

Because the cause of interstitial cystitis is unknown, empirical therapy has had varying success. Oral medications have given relief to some patients and are commonly the first-line regimen tried, but as a general rule, oral methods are less effective than intravesical therapy. We have used anticholinergics, bladder analgesics, calcium channel blockers, antidepressants, and antihistamines alone and in various combinations, and results have differed widely. Physicians do not talk about achieving a cure when dealing with interstitial cystitis, but certainly long-term remission of symptoms is accomplished in many patients because of (or possibly in spite of) various therapies. All therapies for itnerstitial cystitis are truly a trial-and-error undertaking, but any method that is safe and relieves symptomws will be well-received by the patient.

Bladder Hydrodistention

As noted, this diagnostic procedure sometimes provides symptomatic relief. In 1991, Hanno and Wein¹¹ reported that some patients had short-term relief, but most had relapse of the symptoms within weeks. One of us (D.F.M.) has had experience with several women who underwent hydrodistention, had relief for several months, had recurrence of symptoms, and then obtained long-term relief with a second hydrodistention. Why this procedure may or may not help and which patients have the best chance of positive response are unknown. In most patients, especially those with severe, incapacitating symptoms, the procedure is worth a try, particularly consiering the fact that without cystoscopy and hydrodistention, the diagnosis remains one based on presumption only.

Intravesical Therapy

This approach avoids many of the problems that may accoimpany oral therapy, because so little medication is absorbed through the bladder mucosa. A high concentration of drug is delivered to the inflamed mucosa, but since it remains in the bladder only about 15 minutes, systemic absorption is limited¹². In addition, medication instilled into the bladder exerts its effects directly on the inflammation, with minimal interference with liver or renal function, likelihood of drug interaction, or need for drug metabolism.

Through the years, many agents have been instilled into the bladder in attempts to relieve symptoms. Silver nitrate has long been used, but with inconsistent or poor results¹². Today, the most commonly used intravesical agent is dimethyl sulfoxide (DMSO)^7,11. Its only recognized medical use is in treatment of interstitial cystitis. Althogh DMSO is an anti-inflammatory agent, it seems to have some analgesic and muscle relaxant properties as well. As is true of other therapies for interstitial cystitis, there is no way to predict who may or may not respond to DMSO.

DMSO treatment regimens vary and have included occasional instillation, instillation weekly for six weeks, and (especially in patients who do respond) occasional "booster" doses monthly. There is no uniformity of choice regarding treatment schedule. Most likely, each urologist uses a slightlyl different approach; as yet, there is no "right" way to use DMSO. It is probably safe to say that if a patient does not experience relief within a few treatments, further instillation of DMSO is unlikely to be effective.

In other intravesical methods, other chemicals, singly or in combination, have been added to DMSO, including oxychlorosene sodium (chlorpactin)¹⁰, doxorubicin hydrochloride (Adriamycin, Rubex), BCG live (TICE BCG, TheraCys), and herapin⁷. Unfortunately, results of strict placebo-controlled, double-blind studies are not available. DMSO produces a garliclike taste and odor after instillation and oxychlorosene sodium requires general anesthesia for administration because of pain, both of whic prohibit blinded testing.

Surgery

Surgical approaches have ranged from removal of the ulcers to attempts to partially denervate the bladder with a variety of techniques. Long-term results with all methods have been disappointing¹³. Occasionally, partial cystectomy has been undertaken in patients with severe symptoms that have not responded to any conservative methods. Even with this substantive therapy, failures still occur¹⁴.

Primary care treatment recommendations

Initial treatment of suspected interstitial cystitis may consist of oral medication followed by intravesical DMSO. Patients who do not respond to instillation of DMSO should be referred to a urologist, who will probably perform cystoscopy with bladder hydrodistention and biopsy to confirm the diagnosis. If hydrodistention fails to relieve symptoms, patients are sometimes considered for oxychlorosene sodium therapy. In only the most recalcitrant cases is a surgical approach considered.

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Summary

Interstitial cystitis is fairly common in primary care practices and very common in urology practices. Still, it is probably underdiagnosed. Because symptoms can be confusing, patients are sometimes thought to have psychogenic problems or are treated repeated with antibiotics, despite the absence of evidence of bacterial infection. The key to correct diagnosis is awareness of the condition and its characteristics. In patients who have symptoms that resemble routine cystitis but normal results on urinalysis, interstitial cystitis should be considered as the working diagnosis. This is especially applicable in women, who are affected far more often than men.

Various therapies have been tried, but the cure, like the cause, remains unknown. Many patients respond to some form of therapy and may even hav elong-term remissions. However, arriving at the form of therapy that relieves symptoms in a given patient is often a trial-and-error process. A short-term trial of various methods is warranted initially. Ultimately, however, referral to a urologist may be necessary for definite diagnostic testing and additional therapy.

David F. Mobley, M.D., Neil Baum, M.D.

Dr. Baum is associate clinical professor of urology at Tulane University School of Medicine and Louisiana State University School of Medicine, both in New Orleans.

Dr. Mobley is chief, section of urology, Memorial Hosptial, Houston, and Dr. Baum (right) is clinical associate professor of urology, Tulane University School of Medicine and Louisiana State University School of Medicine, New Orleans.

References

¹ Hunner GL. A rare type of bladder ulcer in women, report of cases. Boston Med Surg 1915; 172:660-4.
² Parsons CL, Lilly JD, Stein P. Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis)

Remaining references not available.

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Interstitial cystitis: When urgency and frequency mean more than routine inflammation

Possible Causes

Patient characteristics

Risk factors

Diagnosis

Patient criteria for NIDDK study of interstitial cystitis

NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases Adapted from Interstitial Cystitis, Bethesda: National Institute of Diabetes and Digestive and Kidney Diseases (NIH publication No. 94-3220).

Coping tips for patients with interstitial cystitis

Treatment methods.

Summary

David F. Mobley, M.D., Neil Baum, M.D.

References

NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases
Adapted from Interstitial Cystitis, Bethesda: National Institute of Diabetes and
Digestive and Kidney Diseases (NIH publication No. 94-3220).