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Interstitial cystitis and frequency–urgency syndrome (OAB syndrome)

2003; Wiley; Volume: 10; Issue: s1 Linguagem: Inglês

10.1046/j.1442-2042.10.s1.14.x

1442-2042

Tomohiro Ueda, Grannum R. Sant, Philip M. Hanno, Naoki Yoshimura,

Urinary Tract Infections Management

Women frequently visit urologists or gynecologists complaining of urinary frequency or urgency. The epidemiological study in Kouga County, Shiga, Japan shows that 20% of women in their 40s and as high as 30% of elderly women over 65 experience urinary frequency or urgency, indicating that these are very common symptoms.1 To our surprise, however, it has become increasingly obvious that some women do not go to see a medical specialist even though they suffer from such symptoms, or, even in cases where they do consult a doctor, only antibiotics are prescribed for a presumed diagnosis of bacterial cystitis. Moreover, some women are diagnosed as having anxiety neurosis, depression or psychogenic frequency without an appropriate evaluation or treatment. Of course, going to the toilet dozens of times a day in itself is highly stressful and may well lead to neurosis. Medical specialists are always required to determine whether there is any organic abnormality. For urinary frequency and urgency, however, urologists worldwide tend to make a symptom-based diagnosis. We share this tendency as well in Japan, although it does not identify objective conditions. This attempt has a huge economic and social impact, leading to the development of new drugs in anticipation of a big market for a large number of patients with frequency and urgency problems. In addition, the treatment policy is being changed to focus on alleviation of the symptoms, and a radical cure is not considered crucial, or possible in many cases. In short, the primary goal is to improve subjective symptoms (quality of life). In plain words, the idea to cure a patient rather than a disease, is greatly welcome. First and foremost, a large number of patients suffering from urinary frequency or urgency benefit from the treatment. Every country in the world has its own medical system, and it is a fundamental rule for a patient to receive medical treatment based on a diagnosis. Consequently, this tendency should be highly appreciated, as it will enable a patient to obtain a diagnosis based on symptoms and to more easily receive medical therapy from a primary care physician. However, referral to a specialist should be provided in case medical therapy is not effective. This subject, however, is causing great confusion among urologists around the world, which was triggered by the International Continence Society (ICS) proposal of 2002.2 One of the reasons for the confusion is that in the United States, urinary frequency–urgency syndrome is frequently diagnosed as IC (IC), while in Europe the same symptoms are diagnosed as overactive bladder (OAB). This dichotomy reflects the contrasting approaches of the ICS/WHO and ICA/NIH. This leads to the possibility that the same patient group could be diagnosed differently according to each organization. Without wishing to make excuses, I believe it is more than fair to state in advance that the content of this report is subject to change in the near future due to its controversial nature. Urinary frequency–urgency syndrome is the name used to identify a patient group who suffer from urinary frequency or urgency. The causes remain unknown and the name is based primarily on the symptoms. If frequent urination presents, it is named ‘urinary frequency’, and if urgent need to urinate presents, it is named ‘urinary urgency’. As I mentioned above, ICS announced in 2002 that urinary urgency, with or without urge incontinence, usually with frequency and night-time urination could be described as OAB syndrome, urge syndrome, or frequency–urgency syndrome.2 The problem lies in the conditional clause of the announcement. It said that if a patient has the above mentioned symptoms, detrusor overactivity is usually suspected through urodynamics study, but in a case where there is no presence of infection or other diseases that may cause detrusor overactivity, we can use the names of the above mentioned syndromes. According to this clause, if a patient with the symptoms above has an enlarged prostate, urethral stricture, an impaired sphincter muscle, neurogenic bladder, or genital prolapse, it should not be described as OAB. OAB is the name of a set of symptoms, not a disease. OAB is OAB with or without urethral stricture or other infections. OAB is simply a group of symptoms and not a disease entity.3 There is another issue causing confusion.4 Interstitial cystitis, once called frequency–urgency syndrome or painful bladder syndrome because it presents the symptom of urinary frequency or urgency, has become diagnosed based on symptoms. It is a syndrome diagnosed after ruling out other diseases with evident causes, as in the case of OAB. There is a misconception about IC both in Japan and overseas. It has been believed that IC is a very rare disease characterized by the presence of Hunner's ulcer in a bladder.5 The concept of the disease, formed in the last century, is very old, and has been greatly revised by the US urologists after the consensus-building conference hosted by NIH in 19886 and the following data-based studies.7 It has been revealed that IC is a very common disease.8–11 Interstitial cystitis is a refractory inflammatory disease of the bladder whose cause is unknown.4 It is a non-bacterial cystitis and does not respond to conventional antibiotic therapy. Patients with IC complaining of urinary frequency, urgency, or bladder pain have sometimes been diagnosed as having a psychosomatic disorder because they test negative for infection. Against such unjust treatment, a patient and also a medical doctor, Vicki Ratner, founded the Interstitial Cystitis Association (ICA: http:www.ichelp.com) in 1984,12 which influenced the National Institutes of Health (NIH) and sought funding for research.4 In 1988, the NIH established the first research criteria for IC (Table 1).6 The research and treatment for IC has been developed for the past 15 years primarily in Europe and the United States, and it has been proved that there perhaps a million patients with IC in the United States.10 However, the initial research criteria was very strict, causing 60% of probable IC patients to fail to meet them.7 A movement to establish new international criteria has begun. ICS has given first priority to objective diagnosis for urinary frequency, urgency, and incontinence (this attitude still remains), and defined uninhibited bladder contraction when measuring the pressure of the bladder as a typical case of OAB.13 However, it does not apply to a clinical setting, because in that case the disease cannot be diagnosed in a general clinic without a urodynamics unit. In addition, it became obvious that OAB, whose typical case displays detrusor overactivity alone, could never describe the symptoms of urinary frequency, and urgency.14 Against this background, the International Consultation on Interstitial Cystitis, Japan (ICICJ) was held on March 28–30, 2003 inviting 30 IC specialists from 15 countries of five continents,15 http:www.ichelp.comcafeicaVol03No03.html♯2.1 http:www.interstitial-cystitis.orgjapan1202.html We invited key members of ICS with the intention of providing information on IC for them. At the meeting we could not reach a consensus on the new diagnostic criteria for IC. However, we shared an understanding about symptom-based diagnosis, and it was decided that we could make a diagnosis of IC for a patient who has urinary frequency or urgency with or without bladder pain, when there is no presence of other diseases with evident cause, as in the case of OAB. Again, urinary frequency and urgency are symptoms, not a disease. Consequently, the syndromes shown in Table 2 are uncategorizable uniform syndromes described in different words. As a characteristic found in only Japan, there is nervous pollakisuria, which is a frequent urination (urge to urinate, repeatedly going to the toilet, or urinating) caused by psychological stress.16 The patient needs to urinate during waking hours to experience a sense of satisfaction with the condition of emptied bladder. If urinary frequency has become a habit from childhood, the stress often comes from the behavior of repeatedly going to the toilet itself (physical stress). In some cases, the patient is unable to urinate outside of the home, being oversensitive to what other people think of her/him repeatedly going to the toilet. In other cases, the patient feels urinary urgency only because there is not a toilet around. This syndrome is characterized by its absence of organic lesion in bladder or urethra. Therefore, in order to categorize a condition as nervous pollakisuria, I think it a specialist's role to accumulate objective data from cystoscopy and urodynamic tests. If urinary frequency or urgency continues for about three months without any improvement as a result of the treatment for other diseases with evident cause, the possibility of IC should be considered. Symptom questionnaire is very useful procedure not only to know the outcome measure for IC clinical trials, but also to diagnose the disease. There are two validated instructions, one is the O’Leary–Sant Symptom/Problem index (Tables 3,4)17–19 and the other is the University of Wiscosin symptom score;20,21 it is very useful when taking a medical history of a patient. The characteristic symptom of IC is a pain in the bladder when it is filled with urine. The problem is that the symptom score of IC is identical to that of urinary frequency and urgency. Clinically speaking, a patient's condition diagnosed as OAB is identical to the one diagnosed as IC. If a patient is diagnosed as OAB, anticholinergic medication is the first choice for treatment.22–24 The cure rate is 50% at the maximum. It is not effective for IC, however, the symptoms will be slightly improved. About 18% of IC patients have bladder instability on urodynamics.25 Recently, when the article on the symptoms of IC appeared in a major newspaper, more than 400 inquiries were received within a few days, indicating there are more prospective patients of the disease than expected. Most of the patients, who go to a major hospital regularly, complained of their doctors’ not listening to them sufficiently. They have been repeatedly diagnosed as normal in spite of their existent symptoms. Making a diagnosis of OAB or IC has achieved a breakthrough in such medical situations. It is essential for a medical specialist to take sufficient time in listening to a patient's complaints with symptoms of urinary frequency or urgency.26–28 This is an essential process to examine the patient's lower urinary tract.29,30 The patient records the time and the amount of urine each time the patient goes to the toilet. It is advisable to make recordings at least three days a week.31 If an increase in the total number of voids or a decrease in the volume per void can be detected, this can be the cause of the frequency–urgency syndrome. The diary is one of the most important objective data on the patient. If the patient is referred to urologists, it is advisable to attach this voiding diary to the letter of referral. This is one of the most important tests, as cystitis is the most likely disease when the patient suffers from the frequency–urgency syndrome or urinary incontinence.32 When treatment with antibiotics is not effective, it is advisable to refer to a urologist.33 This is an effective test to identify the urinary dysfunction.34–36 If the postvoid residual urine volume (PVR) is more than 50 mL, the result is regarded as positive. The PVR is measured by using a catheter, which is inserted into the urethra after urination, or by ultrasonography, which is a non-invasive method.37 Some amount of residual urine can cause the frequency–urgency syndrome.38 Treatments to inhibit the bladder contraction can cause increase of the PVR. This test will make it possible to identify urinary calculus, urothelial tumor and, to some extent, neurogenic bladder such as deformed bladder.39 Hydrodistention and Glomerulation. (a) This is a picture by cystoscopy before the bladder is extended. It is extremely difficult to detect abnormality by the examination for outpatients. You have to provide further examination and observe carefully, and then you can detect the increase of coiled new vessels caused by interstitial cystitis. The camera should be fixed and record the same place of the bladder wall. (b) As the bladder is extended, muscle fiber bands appear. These are histologically smooth muscles. We can see parts of the vessels are blocked. Probably the pain caused by extension is partly due to this vessel blockage. Cystoscopy for outpatients cannot be performed further because of the pain. (c) We fill the bladder with liquid at (or to?) a pressure of 80 cm H2O. When the bladder is filled, most of the time, the dropping naturally stops or the fluid begins to leak around the cystoscope, and we start discharge the liquid little by little. As the bladder is being emptied, the blood begins to flow and bleeding occurs gradually beginning at the distal vessels. (d) These are glomerulations, or pinpoint hemorrhages, and a typical symptom of the IC patients. However, the OAB patients may also present the same symptom by hydrodistention under anesthesia. This means the symptom of the IC patients is very common. With this test, doctors may not detect any problems unless the bladder is fully stretched by filling it with liquid under anesthesia. If the bladder is observed carefully, many coiled new vessels or submucosal hemhorrhages related with overexpression of angiogenic factor can be detected. This is highly suggestive of IC.40 In fact, even urologists can often overlook the first stage of IC. If uninhibited bladder contraction is detected when measuring the pressure of the bladder filled with liquid, the patient may be diagnosed with detrusor overactivity. When neurological disorders are obviously detected at the same time, the disease is categorized as neurogenic detrusor overcapacity, and when any cause cannot be detected, this is categorized as essential detrusor overactivity.41 If urinary frequency or urgency is present for more than three months and the cause cannot be identified, the patient can be diagnosed with the frequency–urgency syndrome. The first thing for doctors to do is to rule out the possibilities of other diseases. The most likely other disease is bacterial cystitis. If white blood cells are detected in the urinary sediment and bacteria in a concentration of 10 to the 4th power is detected in a mL of the cultured urine, the patient is probably suffering from bacterial cystitis.42,43 However, if no improvement can be shown with medication, introduction to specialists is needed. Next, the patient may be suffering from detrusor overactivity if uninhibited contraction can be detected when measuring the pressure of the bladder filled with liquid. However, at clinics where there is no facility for measuring the bladder pressure, this cannot be diagnosed. To detect the possibility of bladder cancer (cancer in situ), biopsy (histologic examination) is needed. Urinary cytology is also effective. In addition, the possibilities of radiation cystitis and virus-associated cystitis, which can be detected by taking a medical history, should be excluded. Neurogenic bladder caused by brain and spinal cord diseases such as cerebral infarction or spinal canal stenosis should also be excluded. As well, the possibility of organic disorder such as cystolish or urethral diverticulum should be excluded. Nervous pollakisuria should be diagnosed carefully. The following are indications of nervous pollakisuria: (1) No abnormality can be detected in the urinalysis or the bladder capacity; (2) Frequent urination does not occur when the patient is absorbed in something or during the night. When suffering from insomnia, the patient often experiences frequent urination at midnight. However, the need to urinate does not cause awakening, but often awakening causes the need to urinate; (3) The patient frequently goes to the toilet, but does not suffer from urinary incontinence or leakage; (4) The patient does not suffer from bladder pain, even with a full bladder; (5) The patient has no complications or previous history of related diseases. The appearance is very healthy. Lastly, to diagnose as interstitial cystitis, dilation of the bladder under anesthesia with liquid (hydrodistention) is an effective method. For frequency–urgency syndrome, hydrodistention under anesthesia is most effective. This procedure may alleviate the symptoms, though only temporarily. Pictures of the bladder tend to leave a strong image in the minds of clinicians, and a video tape recording and photography is recommended (Fig. 1). It is better to make all these diagnosis before any treatment is implemented. However, it may be more practical to diagnose and exclude unlikely possibilities one by one, implementing the treatment and waiting to see its effect. Treatment procedures are now being established in many countries. This is a reasonable approach, considering the frequency–urgency syndrome can be diagnosed by excluding other disease possibilities. The basic treatment is to prescribe medication to suppress the bladder overactivity in patients with suspected bladder hyperactivity or instability. Anticholinergic drugs are the first choice, as either normal or abnormal contractions of the bladder smooth muscles are induced by acetylcholine and muscarinic receptors. Meanwhile, it has been found that sensory sensitivity caused by diseases such as chronic cystitis is closely related with C-afferent nerve fibers.44,45 Mechanisms of the receptors and channels of the C-afferent fibers have been made clear, which has encouraged the development of new classes of drugs. 46,47 This is the first choice, it is important not to use these drugs with a vague purpose48,49 (oxybutynin,50,51 propiverine,52–54 tolterodine,55,56 trospium chloride,57,58 YM905,59 and UK88525). Tricyclic antidepressants are effective to control urinary frequency at night and to increase capacity.60,61 It is also certain that these drugs are effective for nervous pollakisuria. However, there are problematic side-effects such as dry mouth and drowsiness (imipramine). (fluvoxamine)62 This drug inhibits the re-uptake of noradrenaline as well as serotonin. Also, following side-effects are reduced:63,64 Cholinergic side-effects from tricyclic antidepressants such as dry mouth and constipation, antihistaminic side-effects such as drowsiness, and alpha 1 adrenolytic side-effects such as orthostatic hypotension. In addition, unlike SSRI, SNRI does not inhibit cytochrome P450 so much, thus SNRI is said to be the safest medicine in terms of drug interactions.65 69,70 The frequency–urgency syndrome is often caused by chronic bladder inflammation, and the chronic inflammation is said to be mainly caused by mast cells, especially histamine released from the mast cells.71–73 This drug is authorized as antiallergic,74–77 but is also found to be effective with the frequency–urgency syndrome and pain in the bladder.78 Currently, it is under the clinical trial pending authorization in Japan and the USA. (pentosan polysulfate sodium): This is the only oral medicine authorized by the FDA for treatment of the pain associated with interstitial cystitis.79,80 This has not been authorized in Japan as yet. The general treatment on IC is to stabilize activated bladder mast cells and replenish deficient GAG layer. Following are such drugs: NS-7201 (sodium hyaluronate): This medicine is ligand of CD44 receptors and plays a major role in restoring damaged tissue. This medicine is authorized in the USA. It is used to stabilize mast cells. This medicine is used to replenish deficient GAG layer. This medicine is effective for the frequency–urgency syndrome caused by bladder overactivity related to acetylcholine and muscarinic receptors in the bladder. (non-irritating capsaicin analog): This medicine is effective for the frequency–urgency syndrome and works at the level of the bladder sensory (C-fiber) afferent nerves.81 (oxybutynin): This medicine has less anticholinergic side-effects and increases organic specificity of the bladder. This therapy has only a temporary effect on urinary frequency and urgency, but is useful in the diagnosis of IC. The procedure is as same as TUR-BT. Fill the bladder with Uromatic S (3000 mL/pack of 3% D-Sorbitol solution by Baxter Healthcare Co.) at (or to?) 80 cm H2O pressure. Make a video record from the time when inserting a cystoscope. Drop speed is approximately 30 mL/min. During this procedure, the cystoscope should be fixed at back or side walls where new blood vessels are visible. Fill the bladder with Uromatic S until it began to leak from the urethra around the cystoscope. At this time, do not rush and let the liquid out. Keep the cystoscope fixed at the same position. Close the inlet of Uromatic S. (Stop dropping.); Slowly discharge the liquid from the bladder at 30 mL/min. Keep the cystoscope fixed and continue to video-record the same mucosal wall even when discharging the liquid. When the bladder is emptied, you may see a lot of glomerulations on the wall. Be sure to measure the amount of liquid discharged from the bladder with a stainless-steel cup. If the amount is 200 mL, the maximum amount of urine discharged after the surgical treatment would be 100 mL. Slowly and carefully repeat the procedure, expanding the bladder several times. If you can expand the bladder to the size of 350–400 mL, the procedure is regarded as optimal. I suppose that glomerulation is created due to the rupture of new vessels. Just providing this procedure would release patients from the pain. However, if the amount of urine decreases to less than 150 mL, symptoms can easily recur. Clinicians need to instruct the patients to take in enough liquid and to try keeping the amount of urine to more than 150 mL for a single time. This procedure is effective to urinary frequency and urgency as well as bladder pain. Clinicians usually stimulate the perineum, dermis, or sacral nerves.83 Two major groups in the world, the International Continence Society (ICS) in Europe and the National Institute of Health (NIH) in the USA, had almost the same definition for overactive bladder (OAB) and IC. However, ICS recently presented a more distinct definition for IC, using the term, painful bladder syndrome. It states that the main symptom of IC is bladder pain when the bladder is filled. This diagnosis standard is very strict, dating back to the standard set in 1988 by the National Institute for Diabetes and Digestive and Kidney Disease (NIDDK). ICS tends to categorize the patients not diagnosed with IC as OAB patients. On the other hand, the group in the USA tends to categorize IC patients from a wider point of view. I think their differences will increasingly confuse clinicians (Table 5). Prior to ICICJ, I proclaimed that IC is a common disease and we need the common pathology to be explained to the world in simple terms. We propose the cause of OAB including IC (Table 6). The International Consultation on Urinary Incontinence 2004 (Monaco) hosted by WHO/ICS recently created a working group on IC. I believe this will help establish a standard diagnostic evaluation threw the effects of the working group chaired by Dr Hanno.