Painful bladder syndrome and interstitial cystitis - Obstetrics and ...

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10.1576/toag.9.1.034.27294 www.rcog.org.uk/togonline

The Obstetrician & Gynaecologist

Review Painful bladder syndrome and interstitial cystitis Authors Swati Jha / Matthew Parsons / Philip Toozs-Hobson

Key content: • Painful bladder syndrome is a chronic disabling condition that mainly affects women. • The aetiology is uncertain, but is almost certainly multi-factorial and presents as a triad of pain, urinary urgency and frequency. • The most common diagnosis made is interstitial cystitis. Diagnosis is based on history and examination and supplemented by clinical investigation.

Learning objectives: • To be able to identify the clinical features of interstitial cystitis and arrange appropriate diagnostic tests. • To know how to manage interstitial cystitis using non-pharmacological, dietary and behavioural treatment, as well as pharmacological and surgical therapy.

Ethical issues: • How much information should women be given about possible adverse effects? Keywords: interstitial cystitis / painful bladder syndrome / pelvic pain / urinary frequency / urinary urgency Please cite this article as: Jha S, Parsons M, Toozs-Hobson P. Painful bladder syndrome and interstitial cystitis. The Obstetrician & Gynaecologist 2007;9:34–41.

Author details Swati Jha MD MRCOG Specialist Registrar in Obstetrics and Gynaecology Department of Urogynaecology Birmingham Women’s Hospital, Metchley Park Road Birmingham, B15 2TG, UK

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Matthew Parsons MRCOG Consultant Obstetrician and Gynaecologist Department of Urogynaecology Birmingham Women’s Hospital Metchley Park Road Birmingham, B15 2TG, UK Email: [email protected] (corresponding author)

Philip Toozs-Hobson MD MRCOG Consultant Obstetrician and Gynaecologist Department of Urogynaecology Birmingham Women’s Hospital, Metchley Park Road Birmingham, B15 2TG. UK

© 2007 Royal College of Obstetricians and Gynaecologists

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Introduction Painful bladder syndrome (PBS) is categorised by suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency in the absence of proven urinary tract infection or other pathology.1 The International Continence Society believes this to be a preferable term to interstitial cystitis. In the past the two terminologies have been used interchangeably. Painful bladder syndrome (Table 1) encompasses a much broader range of causes that need to be excluded, such as carcinoma in situ and endometriosis (Figure 1). There is considerable overlap between the overactive bladder syndrome (OAB), the urethral pain syndrome (urethral syndrome) and PBS. Whereas the principal complaint of women with OAB is urgency, in women with PBS it is predominantly pain related to bladder filling (Figure 2). Women with urethral pain syndrome, on the other hand, complain of pain on voiding. The term PBS, therefore, includes cases with painful urinary symptoms that may not meet the strictest definition of interstitial cystitis, for example, radiation cystitis and cyclophosphamide cystitis. The term interstitial cystitis is used alone when describing cases that meet all of the interstitial cystitis criteria established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Box 1) and is a diagnosis of exclusion.

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Women between the ages of 40 and 60 years are most commonly affected. The condition occurs far more frequently in Caucasians and there is a 9:1 female predominance.2 Up to 50% of women experience spontaneous remissions unrelated to treatment, with a duration ranging from 1 to 80 months.3 Reported prevalence rates for this condition vary widely as there is no universally accepted definition.

Aetiology The pathophysiology of interstitial cystitis remains elusive and many theories have been formulated. A detailed discussion of the aetiology is outside the scope of this article. Bladder wall dysfunction and GAG layer deficiency Dysfunctional lower urinary tract epithelium is said to be characterised by damage to the glycosaminoglycans (GAG) layer.4 This can lead to increased permeability to potassium, which then permeates the bladder musculature, triggering imperative urgency and bladder contractions. Mast cell activation is considered to be a result of GAG layer deficiency: this provokes a neurogenic inflammation with overexpression of neurotransmitters. This remains controversial and, as yet, unconfirmed by electron microscopy.

Figure 1

Interstitial cystitis: part of the disease spectrum of painful bladder syndrome

The aim of this review is to summarise the presentation, investigation and management of women with interstitial cystitis.

Interstitial cystitis Interstitial cystitis is a chronic inflammatory disorder of the bladder and one of the causes of PBS first described by Hunner in 1915. It results in consistently low quality-of-life scores, is notoriously difficult to manage and can cause considerable morbidity.

Differential diagnosis of PBS

Methods of investigation

Bladder cancer Infection with common intestinal bacteria Infection with Mycobacterium tuberculosis, Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalis Corynebacterium urealyticum, candida, herpes simplex, human papilloma virus Radiation/chemotherapy/ immunotherapy with cyclophosphamide/ anti-inflammatory therapy with tiaprofenic acid Bladder neck obstruction Neurogenic outlet obstruction Bladder/lower ureteric stone

Cystoscopy and biopsy Culture and sensitivity Dipstick test for M. tuberculosis: if negative, culture for other atypical organisms

Urethral diverticulum Endometriosis Vaginal candidiasis Cervical, uterine and ovarian cancer Incomplete bladder emptying (retention)


Table 1

Differential diagnosis of painful bladder syndrome and methods of investigation

History Flowmetry and ultrasound History, flowmetry and ultrasound Imaging or cystoscopy History and/or haematuria (upper urinary tract imaging such as CT [computed tomography] scanning/or intravenous pyelogram) History, physical examination and imaging History, physical examination and laparoscopy History and physical examination History, physical examination and imaging Post-void residual urine volume

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Figure 2

Illustration of build-up of sensation proceeding through discomfort to pain in patients with painful bladder syndrome.45 Reprinted with permission of Wiley–Liss, Inc. a subsidiary of John Wiley & Sons.

e

ladder

Box 1

Criteria for the diagnosis of interstitial cystitis

NIDDK initial criteria (1987)

certain HLA groups, allergies and autoimmune processes.5,6

Automatic diagnosis: Hunner’s ulcer Positive factors (two needed): • Pain on filling, relieved by emptying • Suprapubic, pelvic, vaginal or perineal pain • Glomerulations on endoscopy • Decreased cystometric compliance NIDDK revised criteria (1988)

Hypoxia Vascular, hormonal or toxic factors leading to bladder wall hypoxia may affect the GAG layer.7 A reduced blood flow in the suburothelial layers (but not deeper layers) has been seen in women with interstitial cystitis.

Presence of bladder pain or urinary urgency Glomerulations or Hunner’s ulcer Exclusions: • Cystometric (awake) capacity 350 ml ° Using fill rate 30–100 ml/minute, absence of intense urge to void at 100 ml gas or 150 ml liquid • Involuntary contractions on cystometry • Awake frequency 8/day

Visceral hypersensitivity theory Interstitial cystitis has been described as visceral neuropathic pain, a hypersensitive state that is secondary to a site of irritation located in the urinary bladder.8 This may explain the association with other visceral hypersensitivity disorders such as irritable bowel syndrome9 and fibromyalgia.10

• No nocturia • Duration 9 months • Age 18 years • Cystitis (bacterial, chemical, tuberculosis, radiotherapy) • Prostatitis, vaginitis • Bladder, uterine, cervical, vaginal or urethral cancer • Active herpes • Bladder or lower ureteral calculi • Urethral diverticulum NIDDK National Institute of Diabetes and Digestive and Kidney Diseases

Box 2

Investigations for the diagnosis of interstitial cystitis: consensus from international conferences12–14

Mandatory investigations • History and physical examination • Urinalysis, urine culture, urine cytology Optional investigations • Symptom questionnaires • Cystoscopy Specific where indicated • Hydrodistension • Bladder biopsy

Clinical features Pelvic pain, urgency and urinary frequency are essential to support a diagnosis of interstitial cystitis.11 Pain typically occurs in the pelvic area and can manifest in the bladder, vagina, urethra, rectum or perineum. It is chronic and urinary tract infection is absent. It can be sharp in nature but there can also be feelings of pressure or burning. It can also be related to sexual intercourse. However, the characteristic feature is the relationship of pain to bladder filling and relief during voiding. Pain during voiding, on the other hand, is more suggestive of urinary tract infection, vulval or vaginal disorders or the urethral pain syndrome and can occasionally be caused by urethral diverticula.

Investigation and assessment There have been three major conferences recently to try and establish a consensus on the diagnosis of interstitial cystitis.12–14 The diagnostic consensus reached from these meetings is presented in Box 2.

• Urodynamics • Potassium sensitivity test

Autoimmune system disorders Disorders of the immune system are suspected as being causative because of the association with 36

Pelvic examination Pelvic examination is of limited value in making a positive diagnosis of interstitial cystitis. The bladder can occasionally be tender on palpation but the examination is helpful in excluding other conditions that can cause similar symptoms.


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Physical examination should include a vaginal examination with pain mapping of the vulval region and vaginal palpation for tenderness of the bladder, urethra, levator and adductor muscles of the pelvic floor and pelvic organs. Pain mapping of the vulva requires the exclusion of vulvar/vestibular diseases by the touch test (using a wet cotton stick or fingertip). This consists of the palpation of six randomly ordered vestibular sites with a cotton swab.15 Voiding diary This is an important tool in the investigation of lower urinary tract symptoms. For a voiding diary to have value it must be completed correctly. A 3-day diary has been suggested as optimal.16 It is usual to see women with interstitial cystitis having frequent, small volume voids. Urine testing Urinalysis is usually normal in interstitial cystitis. Haematuria can be present but other causes should be excluded. Urine culture is essential to exclude simple urinary tract infection. Culture and sensitivity should be done for atypical infections such as Ureaplasma urealyticum, Mycoplasma hominis or Chlamydia trachomatis. Urine cytology is recommended if haematuria is present or where risk factors for bladder cancer are identified (smoking, age above 50 years, family history or occupational exposure to certain industrial chemicals such as aromatic amines).17 Questionnaires and symptom scales To date there are three published questionnaires for use in interstitial cystitis: the University of

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Wisconsin Interstitial Cystitis Scale,18 the O’Leary–Sant Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index19 and the Pelvic Pain and Urgency/Frequency (PUF) Scale.20 The general consensus of an expert panel in Kyoto was that none of the scales could be used for diagnosis, although they can be valuable in monitoring the progress of treatment outcomes.12 Urine markers Urine markers show promise in the assessment and diagnosis of interstitial cystitis. Certain markers are significantly increased in interstitial cystitis, including antiproliferative factor, epidermal growth factor, insulin-like growth factor (IGF) binding protein-3, interleukin (IL)-6 and nitric oxide.21 Antiproliferative factor is the most likely candidate to become a diagnostic test, with the least overlap between interstitial cystitis and control groups.22 However, none of these markers are routinely used for the diagnosis of interstitial cystitis. Research is under way to test their usefulness in clinical practice. Urodynamics Urodynamics is used to rule out alternative pathology such as obstructed voiding or detrusor overactivity, rather than positively diagnose interstitial cystitis. Hypersensitivity during filling cystometry, a small bladder capacity, reduced maximal flow rate and abnormal flow pattern have been observed in women with interstitial cystitis. These findings are not specific and can also be encountered women without interstitial cystitis.23 Interestingly, 14% of patients with interstitial Figure 3

Cystoscopic findings of interstitial cystitis


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cystitis have evidence of detrusor overactivity on subtracted cystometry.24 Potassium sensitivity testing This test involves a comparison of pain and urgency sensation after consecutive instillation into the bladder of 40 ml of water and 40 ml of 40 mEq/100 ml potassium chloride for 5 minutes each. A positive test results in an increase in pain with potassium chloride. Potassium sensitivity testing does not correlate to bladder capacity or cystoscopic findings, hence is of limited value in the diagnosis of interstitial cystitis.25 It is not part of the routine assessment of painful bladder symptoms in the UK and attempts to modify the test so that it is more comfortable for women are under way.26 Cystoscopy In 1915 Hunner described the ulcers,consisting of glomerulations and small,discrete purple haemorrhages of the bladder mucosa,that are often found in women with interstitial cystitis.However, women with interstitial cystitis can have a normal appearance to the urothelium.The purpose of cystoscopy in the investigation of bladder pain is the exclusion of local,intravesical abnormalities (Figure 3). The decision for cystoscopy is frequently based on the presence or absence of risk factors for bladder cancer. One percent of women with interstitial cystitis in a tertiary unit in the US were eventually diagnosed with transitional cell carcinoma of the bladder17 and some authors advocate cystoscopy as a mandatory investigation.14

Non-pharmacological

Avoidance of trigger foods Dietary supplementation Stress relieving exercises Transcutaneous nerve stimulation (TENS)

Oral medication

Antihistamines Antidepressants Cimetidine Sodium pentosanpolysulfate (Elmiron) L-arginine Prelief Oxybutinin Antibiotics Methenamine (Hiprex)

Drugs for bladder instillation

Hyaluronic acid (Cystistat) Chondroitin sulphate (Uracyst) Dimethyl sulfoxide (DMSO) Intravesical heparin Hydrodistension

Surgery

Partial cystectomy Augmentation cystoplasty

Common pathological findings include epithelial denudation or ulceration, mononuclear inflammation, oedema, congestion, haemorrhage and mast cell activation. The mast cell activation is estimated on histology by mast cell count: >28/mm2 or >12/high power field being thought significant.17 However, these histological features are not pathognomic for interstitial cystitis and the prognostic features of inflammatory markers are not known. Mast cell activity, however, is thought to relate to disease activity,the sequel being long-term fibrosis.27 Cystoscopic appearances do not appear to identify a distinct pathophysiological subset of women with interstitial cystitis symptoms. Women who have typical cystoscopic findings for interstitial cystitis have worse daytime frequency, nocturia and lower bladder capacity under anaesthesia than those who do not. However, the groups have similar urine markers and bladder biopsy findings.28

Management Management of women with interstitial cystitis (Box 3) remains a therapeutic dilemma. A total of 183 different types of therapies have been recorded, suggesting that there is no simple solution.29 Management begins with initial assessment, acknowledging and validating pain and setting expectations.30 Single drug therapy is sufficient for most women, but multi-modal therapy can be appropriate for those with severe or longstanding disease. In most studies involving placebo controlled trials there has been a demonstrable benefit in the placebo arm. Non-pharmacological treatments A major part of the management of women with interstitial cystitis is behavioural and nonpharmacological. Strategies such as physical therapy, avoidance of flare inducing foods (such as those with high acidity or a high potassium content. See Table 2), bladder training and stress management techniques can supplement pharmacological treatment and improve clinical response.31 Pharmacological treatments Attempting to address all aspects of pain management is beyond the scope of this review. The current pharmacological options available specifically for managing interstitial cystitis pain are outlined here, including some new developments. Pharmacotherapy in interstitial cystitis is based on four principles:

• controlling a dysfunctional urothelium by

Urinary diversion

Box 3

Management options for interstitial cystitis

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• • •

restoring the mucus/GAG layer with GAG or GAG-like drugs inhibiting neurological activity suppression of allergies pain control. © 2007 Royal College of Obstetricians and Gynaecologists

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Food group

‘Permitted’

Avoid

Beverages

Bottled water, red bush tea, pear juice

Breads

White bread, rice bread/cakes, millet, buckwheat, matzo, plain pita Refined, rice, plain pasta Butter, margarine, vegetable oils Soups made with allowed vegetables Beef, chicken, lamb, veal, flounder, halibut, salmon, snapper, scallops, sole, mackerel, tuna, crab, shrimp

Alcoholic beverages (including beer and wine); carbonated drinks such as sodas; coffee or tea; fruit juices, especially citrus or cranberry Rye and sourdough

Grains Fats Soups Meat, fish and poultry

Cheese/dairy Vegetables

Beans Fruits

Sweets Spices

Nuts

Cream cheese, cottage cheese, ricotta, milk Alfalfa, beets, broccoli, Brussels sprouts, chicory, carrots, celery, cucumber, cauliflower, okra (lady’s fingers), courgettes, squash, turnips, kale, leeks Aduki, navy, chick peas, split peas, kidney, peas Apples, apricots, avocados, bananas, cantaloupes, citrus fruits, cranberries, grapes, nectarines, peaches, pineapples, plums, pomegranates, rhubarb, strawberries and juices made from these fruits White chocolate, frozen yogurt Rosemary, thyme, oregano, basil, marjoram, fennel, sage, dill, mixed herbs

Pine, cashews, almonds

Oral medication Antihistamines Histamine is an enzyme that causes an increase in the internal dimensions of the blood vessels. Antihistamines have been shown to be useful for the symptomatic treatment of interstitial cystitis, especially in women with documented allergies or evidence of bladder mast cell activation, perhaps by preventing the release of histamines that can cause inflammation.32 In the immediate term it can improve nocturia. Sufferers of interstitial cystitis should normally see an improvement within approximately 6–8 weeks of continuous use. Cimetidine More commonly used for healing stomach ulcers, this drug has also been found to be effective at controlling some symptoms of interstitial cystitis.33 Amitriptyline Amitriptyline is frequently used in pain management. Anecdotal experiences with the tricyclic class of antidepressants suggest that amitriptyline can be an effective treatment modality in non-ulcerative interstitial cystitis. In a prospective study34 examining the safety and efficacy of amitriptyline in women with interstitial cystitis, a significant change in the symptom score and improvement of pain and urgency intensity compared with placebo was observed. Sodium pentosanpolysulfate (Elmiron®) This acts by substituting a defective glycosaminoglycan layer and inhibiting complement reactions in inflammatory processes. It is the only oral agent used to treat interstitial cystitis that has been rigorously investigated in double blind trials.35 The most common adverse effect is diarrhoea. Because less than 10% of the drug is excreted through the urine and rebuilding the glycosaminoglycan layer is a slow process, it © 2007 Royal College of Obstetricians and Gynaecologists

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Table 2

Dietary advice for interstitial cystitis sufferers31

Canned, cured, processed or smoked meats and fish, anchovies, caviar, chicken livers, corned beef and meats that contain nitrates or nitrites Aged cheeses, sour cream, yogurt Onions and tomatoes

Fava beans, lima beans, soy beans, tofu Melons (other than cantaloupes) blueberries and pears

Chocolate, sugars, artificial sweeteners Mayonnaise, ketchup, mustard, salsa, spicy foods (especially ethnic foods such as Chinese, Indian, Mexican and Thai), soy sauce, salad dressing and vinegar, including balsamic and flavoured vinegars Most nuts

takes time for the drug to work. Some response usually occurs within 4 weeks but treatment should be continued for a minimum of 3 months. It is taken in capsule form, usually in doses of 100–200 mg, 3 times a day. It should not be taken with meals but preferably 1 hour before or 2 hours after eating. It is not currently licensed in the UK. L-arginine L-arginine increases the amount of nitric oxide in the urine of women with interstitial cystitis. Symptoms of pain and frequency may improve.36 This may be caused by the bladder’s blood supply being improved by increased levels of nitric oxide within its tissues. The recommended dose is 1.5 g per day. It is not a drug as such and, therefore, does not require a prescription. It can be obtained in most health food shops and some pharmacies and it can also be taken in conjunction with standard medical treatments for interstitial cystitis. Prelief Prelief® (AkPharma, Pleasantville, NJ) contains calcium glycerophosphate, a food-grade mineral classified as a dietary supplement, which can be used with acidic foods and beverages to make eating more comfortable.37 The dose is two tablets three times a day; it is best to take them with meals. It is not currently available in the UK. Drugs used for bladder instillation Hyaluronic acid Hyaluronic acid (Cystistat,® Bioniche Life Sciences Inc, Belleville, Ontario) is licensed for use in the UK. It temporarily replaces the deficient GAG layer on the bladder wall, helping to relieve the pain, frequency and urgency of interstitial cystitis. For the first 4 weeks of treatment, women with interstitial cystitis receive one instillation each week. After that, treatments are usually given once a month until the symptoms resolve. 39

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Response time will vary; however, women who do not notice an early improvement should not be discouraged, as five or six instillations can be necessary before symptoms begin to resolve. Treatment can be repeated if symptoms return. Chondroitin sulphate Chondroitin sulphate (Uracyst,® Stellar Pharmaceuticals Inc, London, Ontario) recently became available in the UK. One study using chondroitin sulphate showed 67% of patients responding favourably.38 The mechanism proposed for the action of hyaluronic acid and chondroitin sulphate is coating of damaged bladder.39 Dimethyl sulfoxide (DMSO) Dimethyl sulfoxide is not licensed in the UK for use in interstitial cystitis. It reduces inflammation by acting as an antioxidant, a scavenger of the free radicals that gather at the site of injury, and by stabilising membranes, which slows or stops leakage from injured cells and which may be useful in restoring the GAG layer. The treatment is usually given for 6–8 weeks at fortnightly intervals. A catheter is placed into the bladder and the DMSO solution is held in place for up to 15 minutes. Some women can find this painful. The solution is then voided. No significant adverse effects of DMSO have been noted, although approximately 20% of women complain of a garlic halitosis. In our experience it is these women who have the best response. Intravesical heparin Heparin is a glycosaminoglycan which can afford protection to the urothelium and which reduces the relapse rate. It is better tolerated than DMSO and does not produce garlic halitosis. It is not associated with coagulation anomalies when administered intravesically and has a response rate of up to 56% of patients.40 Hydrodistension Cystoscopy with hydrodistension is the most commonly performed intervention in women with interstitial cystitis. Hydrodistension is thought to work by disrupting the neuronal pathways of the bladder, thereby disrupting pain transmission. Treatment efficiency ranges from 12–70%.41–42 The benefits are, however, short lived and it can cause ischaemia, damage43 and even bladder rupture44 and is not recommended in our unit. During hydrodistension, the infusion height should be approximately 80 cm above the symphysis pubis, using a dripping chamber until the flow stops and observing for blood vessels, deposits, white spots, hyperaemia, scars, cracks or mucosal changes at the end of the procedure. When maximum capacity is reached, distension is maintained for 3 minutes and the bladder emptied and refilled to around one-third of the maximum for visualisation of haemorrhage and possible 40


biopsy, which should be performed to include detrusor muscle. Surgery Reconstructive surgery is considered where other treatments have failed and symptom severity is such that the woman’s quality of life is seriously affected. Surgery is invasive and irreversible and there is no guarantee that the symptoms will improve. Some can, in fact, become worse. Potential complications from surgical procedures also need to be considered. Options available include partial cystectomy, augmentation cystoplasty and urinary diversion with or without cystectomy. Other less invasive surgical options include endoscopic resection or fulguration of bladder ulcers and local injection of hydrocortisone, saline and heparin in and around the ulcers.

Conclusion The clinical diagnosis of interstitial cystitis is based on identifying symptom criteria and excluding organic disease with diagnostic evaluation. Clinicians should feel secure with the diagnosis of interstitial cystitis, if made properly, because it is rarely associated with other explanations for symptoms. An integrated diagnostic and treatment approach first requires an effective physician–patient relationship. A careful history will also identify the need for diagnostic studies and treatments, depending on the nature and severity of the predominant symptoms and the degree and extent of influencing psychosocial and other factors. The fact that definite structural or biochemical abnormalities for these disorders cannot be detected with conventional diagnostic techniques does not rule out the possibility that neurobiological alterations will eventually be identified to explain fully the symptoms of most functional disorders. As with other chronic illnesses, a multi-component model that involves physiologic, affective, cognitive, and behavioural factors can be formulated for PBS. Instituting a multidisciplinary approach using nonpharmacological and pharmacological therapeutic modalities may result in the most effective outcome. Hopefully, future studies will enhance our understanding of this condition and lead to newer, more effective treatments. References 1 Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:167–78. doi:10.1002/nau.10052 2 Parsons M, Toozs-Hobson P. The investigation and management of interstitial cystitis. J Br Menopause Soc 2005;11:132–9. doi:10.1258/136218005775544255 3 Held PJ. Epidemiology of interstitial cystitis. In: Hanno PM, editor. Interstitial Cystitis. London: Springer–Verlag; 1990. p. 29–48.


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