The challenges in diagnosis and management of interstitial cystitis in women

Introduction
Interstitial cystitis (IC) is a chronic inflammatory disorder of the bladder with typical cystoscopic and/or histological features in the absence of infection or other pathology. It is one of the causes of painful bladder syndrome (PBS) and in the past the two terminologies were used interchangeably.

However, the International Continence Society prefers the term PBS defined as ‘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 term PBS, therefore, includes cases with painful urinary symptoms that may not meet the strictest definition of interstitial cystitis, for example, radiation cystitis, cyclophosphamide cystitis and it encompasses a broader range of causes that need to be excluded e.g. carcinoma in situ and endometriosis. Interstitial cystitis should be used when describing cases that meet all of the IC criteria established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Table 1) and should be a diagnosis of exclusion².

Skene and Hunner were pioneers in the discovery of interstitial cystitis. The name interstitial cystitis was given to the disease in the late 19th century by A.J Skene. In 1914, Guy Hunner described this inflammatory bladder lesion as ulcers in the bladder wall hence the name ‘Hunner’s ulcers’. However, only 5-10% of interstitial cystitis patients have these ulcers, leading to many decades of under-diagnosis.

It’s only in recent years, that IC has been classified into two types – classical or ulcerative and non-ulcerative³. IC is difficult to manage, can be debilitating with considerable morbidity and a poor quality-of-life in affected women. The aim of this review is to summarise the presentation, investigation and management of women with interstitial cystitis.

Epidemiology
Reported prevalence rates for this condition vary widely because of the lack of a uniform, definition, lack of readily available diagnostic markers and overlapping conditions. In addition, the true prevalence of IC is hard to determine as most patients remains undiagnosed although it is thought to occur in up to 7.5% of the general female population and in 38-85% of women who present with chronic pelvic pain⁴. Women between the ages of 40 and 60 years are most commonly affected. The condition occurs far more frequently in Caucasians with a 9:1 female predominance⁵. A recent survey from Finland indicated the prevalence of clinically confirmed probable interstitial cystitis in women was 230 per 100,000 and that of possible/probable interstitial cystitis 530 per 100,000⁶.

Aetiology
The pathophysiology of interstitial cystitis remains elusive and many theories have been proposed with varying degrees of evidence. Some of the proposed theories are as follows.

Bladder wall dysfunction and GAG layer deficiency
The current body of evidence supports the idea that interstitial cystitis is associated with an intrinsic pathology of the bladder urothelial cells. Keay and Warren⁷ have identified a low-molecular-weight peptide termed anti-proliferative factor (APF) in the urine of interstitial cystitis patients that inhibits the proliferation of normal bladder epithelial cells in vitro. The chronically damaged epithelium is prone to colonisation with various micro-organisms, and the resulting exposure to these micro-organisms, other urinary antigens, and / or damaged epithelial cells prompts the low-level inflammatory response commonly seen in this disorder. In addition, dysfunctional lower urinary tract epithelium is said to be characterised by damage to the glycosaminoglycans (GAG) layer⁸. 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. An increased number of mast cells have been associated with interstitial cystitis, but the published reports are inconclusive.

Autoimmune system disorders
Disorders of the immune system are suspected as being causative because of the association with certain HLA groups, allergies and autoimmune processes⁹.

Visceral hypersensitivity theory
Interstitial cystitis has been described as visceral neuropathic pain, a hypersensitive state that is secondary to irritation located in the bladder. This may explain the association with other visceral hypersensitivity disorders such as irritable bowel syndrome and fibromyalgia¹⁰. Furthermore, APF (as mentioned above) regulates expression of other cytokines, which are related to increases in purinergic (adenosine triphosphate) signalling, which could mediate increased bladder sensation¹¹.

Diagnosis and Assessment
Clinical features
Pelvic pain, urgency and urinary frequency are essential to support a diagnosis of interstitial cystitis. Pain typically occurs in the pelvis and can manifest in the bladder, vagina, urethra, rectum or perineum. It can be sharp in nature but there can also be feelings of pressure or burning and can also be related to sexual intercourse. Sometimes, the pain is exacerbated after consuming certain foods especially coffee, alcohol, carbonated drinks, citrus fruits, tomatoes and chocolate³. However, the characteristic feature is that the pain is relieved by voiding but soon recurs as the bladder fills.

It is worth noting that there is considerable overlap between the overactive bladder syndrome (OAB), the urethral pain syndrome (urethral syndrome) and IC. Whereas the principal complaint of women with OAB is urgency, in women with IC it is predominantly pain related to bladder filling. Women with urethral pain syndrome complain of pain on voiding but this can also be due to urinary tract infection, vulva or vaginal disorders or occasionally by a urethral diverticula. Other differential diagnosis of IC are shown in Table 2. The consensus reached from major conferences regarding the assessment needed in establishing a diagnosis of interstitial cystitis is summarised in Box 1 and discussed below^12-14.

Pelvic examination
Pelvic examination is of limited value in making a diagnosis of IC but the examination is helpful in excluding other conditions. Vaginal examination should include palpation for tenderness of the bladder, urethra, levator and adductor muscles of the pelvic floor and vulval pain mapping. Pain mapping of the vulva requires the exclusion of vulvar/vestibular diseases by the touch test (using a wet cotton wool stick or fingertip) to palpate six randomly ordered vestibular sites.

Voiding diary
This is an important tool but needs to be completed correctly; a three day diary is optimal. Women with IC tend to have frequent, small volume voids.

Urine testing
Urinalysis is usually normal in interstitial cystitis with a sterile culture, but it is essential to exclude urinary tract infection which may be present concurrently. Culture and sensitivity should be done for atypical infections such as Ureaplasma urealyticum, Mycoplasma hominis, Mycobacterium tuberculosis and Chlamydia trachomatis. Occasionally, microscopic haematuria or pyuria may be present but other causes should be excluded. Urine cytology is recommended if haematuria is present or where risk factors for bladder cancer are present.

Questionnaires and symptom scales
There are three main questionnaires used in interstitial cystitis: the University of Wisconsin Interstitial Cystitis Scale¹⁵, the O’Leary-Sant Interstitial Cystitis Symptom Index / Interstitial Cystitis Problem Index¹⁶ and the Pelvic Pain and Urgency/Frequency (PUF) Scale¹⁷. The general consensus from expert panel opinion and major conferences is that none of them could be used for diagnosis, although they can be valuable in monitoring the progress of treatment¹².

Urinary markers
Urine markers show promise in the assessment and diagnosis of interstitial cystitis. Certain markers are significantly increased in interstitial cystitis, including anti-proliferative factor (APF), epidermal growth factor (EGF), insulin-like growth factor (IGF) binding protein-3, interleukin (IL)-6 and nitric oxide¹⁸. APF is the most likely candidate to become a diagnostic test, with the least overlap between interstitial cystitis and control groups (p < 0.005, sensitivity, 94%, specificity, 95%)¹⁹. However, none of these markers are routinely used for the diagnosis of interstitial cystitis and the research on their usefulness in clinical practice continues.

Urodynamics
Urodynamics is used to rule out alternative pathology such as voiding dysfunction or detrusor overactivity, rather than 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 be found in women without interstitial cystitis. Interestingly, 14% of patients with interstitial cystitis have evidence of detrusor overactivity²⁰.

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 five 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 and not recommended in the diagnosis of interstitial cystitis.

Cystoscopy/Biopsy
The purpose of cystoscopy in the investigation of bladder pain is the exclusion of local, intravesical abnormalities. Typical cystoscopic appearances can be that of glomerulations, inflammation or Hunner’s ulcers. However, women with IC can have a normal bladder appearance. Glomerulations are small discrete pin-point hemorrhages (petechiae) seen in the bladder mucosa following hydrodistension while Hunner’s ulcers are circumscribed, reddened mucosal areas with small vessels radiating towards a central scar, with a fibrin deposit or coagulum attached.

This site ruptures with increasing bladder distension, with petechial oozing of blood from the lesion and mucosal margins in a waterfall manner. A slightly bullous oedema develops post-distension (Figures 1 and 2). Women who have typical cystoscopic findings for interstitial cystitis have worse daytime frequency, nocturia and lower bladder capacity than those who do not²¹.

A new classification system (see box below) was proposed by Nordling et al to replace glomerulation and ulceration¹⁴.

Histological findings on biopsy include epithelial denudation or ulceration, mononuclear inflammation, oedema, congestion, haemorrhage and mast cell activation. However, they are not pathognomic for interstitial cystitis and the prognostic features of inflammatory markers are not known. Mast cell activity is thought to relate to disease activity, the sequelae being long-term fibrosis. The severity of cystoscopic findings does not correlate with the histological findings²¹.

Management
Management of women with interstitial cystitis remains a therapeutic challenge as no single agent has proven universally effective. As summarised in Box 2, many different types of therapies have been used, suggesting that there is no simple solution. Management begins with initial assessment, acknowledging and validating pain and setting expectations.

Non-pharmacological treatments
A major part of the management of women with interstitial cystitis is behavioural and non-pharmacological. Strategies such as avoidance of flare inducing foods especially those with high acidity or high potassium content like coffee, tea, carbonated drinks, alcoholic beverages, sour cream, onions, tomatoes and canned, processed smoked fish and meat is important. Other strategies include physical therapy, bladder training and stress management techniques to supplement pharmacological treatment and improve clinical response.

Pharmacological treatments
Pharmacotherapy in interstitial cystitis is based on four principles: controlling a dysfunctional urothelium by restoring the GAG layer, inhibiting neurogenic inflammation, suppression of allergies and pain control. Current pharmacological options are outlined below.

Oral medication
Antihistamines
Histamine is an enzyme that causes an increase in the internal dimensions of the blood vessels. Some 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. Cimetidine is a histamine-2 antagonist more commonly used for healing stomach ulcers, but at 400 mg twice daily has been found to be effective²². Suprapubic pain and nocturia were the most improved symptoms. Improvement is usually within six to eight weeks of continuous use.

Amitriptyline
Amitriptyline is frequently used in pain management. It is a tricyclic antidepressant with central and peripheral anticholinergic activity, antihistamine sedation effect and inhibition of serotonin and norepinephrine re-uptake. The recommended dose for interstitial cystitis is 25-100 mg daily, subject to self-titration. A significant change in the symptom score and improvement of pain and urgency intensity compared with placebo was observed in a prospective study²³. Anticholinergic side-effect is the major drawback of treatment.

Sodium pentosanpolysulfate (Elmiron®)
Pentosan polysulphate (PPS) remains the corner-stone of drug therapy for most patients with interstitial cystitis. It is the only US FDA-approved oral treatment for the relief of bladder pain and is the only oral therapy for IC treatment that has been studied in double blind placebo-controlled trials²⁴. PPS is a heparin-like synthetic, polysaccharide that is excreted into the urine. It acts by coating the bladder lining, re-establishing the GAG layer and inhibiting complement reactions in inflammatory processes. As less than 10% of the drug is excreted through the urine, rebuilding the GAG layer is a slow process and it takes time for the drug to work. Some response usually occurs within four weeks but treatment should be continued for a minimum of three months. It is taken in doses of 100-200 mg, three times daily, preferably one hour before or two hours after eating. The most common side effect is diarrhoea.

L-arginine
Nitic oxide (NO) is involved in host defence reactions. L-arginine increases the amount of nitric oxide in the urine of women with interstitial cystitis. Symptoms of pain and frequency may improve, possibly due to 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 hence a prescription is not required. It can be obtained in most health shops or pharmacies and can be taken in conjunction with standard medical treatments for IC.

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. The dose is two tablets three times daily, best taken with meals.

Intravesical treatment
Hyaluronic acid (Cystistat)
Hyaluronic acid 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 four weeks of treatment, women with interstitial cystitis receive one instillation each week. Following that, treatment is usually given once a month until the symptoms resolve. Response time will vary; however, women with no early improvement should not be discouraged, as five or six instillations may be necessary before symptoms begin to resolve. Cystistat produced a 71% response rate at the end of 12 weeks in a trial on refractory IC, although this response rate decreased after six months²⁵. Treatment can be repeated if symptoms return.

Chondroitin sulphate (Uracyst)
Chondroitin sulphate is a naturally occurring mucopolysaccharide which acts by replenishing the glycosaminoglycans at the luminal surface of the bladder. The results of an open-label study showed a good response in 46% of patients and 45% patients had moderate response at 13 months’ follow-up²⁶. Another study by the same authors showed 67% of patients responding favourably²⁷.

Dimethyl sulfoxide (DMSO)
Dimethyl sulfoxide is not licensed in the UK for use in interstitial cystitis. It has anti-inflammatory and analgesic properties. It reduces inflammation by acting as an antioxidant, a scavenger of free radicals, and by stabilising membranes it slows or stops leakage from injured cells, hence may be useful in restoring the GAG layer. The treatment is usually given for six to eight weeks at fortnightly intervals. A catheter is placed into the bladder and the 50% DMSO solution is held in place for up to 15 minutes before voiding. Some women can find it painful with temporary worsening of bladder symptoms (chemical cystitis) lasting 24-72 hours after treatment and approximately 20% of women complain of garlic halitosis for 24 hours.

Intravesical heparin
Heparin is a glycosaminoglycan which can afford protection to the urothelium as it mimics the GAG layer. 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 with continued improvement even after one year²⁸.

Hydrodistension
Cystoscopy with hydrodistension is used for the diagnosis and treatment of interstitial cystitis; it is one of the oldest treatments for 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%²⁹. The benefits are, however, short lived and it can cause ischaemia, damage and even bladder rupture³⁰. 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, hyperaemia, scars, cracks or mucosal changes at the end of the procedure. When maximum capacity is reached, distension is maintained for three minutes and the bladder emptied and refilled to around one-third of its maximum capacity for visualisation of haemorrhage and biopsy if indicated.

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 there is no guarantee that the symptoms will improve while some can become worse. Less invasive surgical options including endoscopic resection or fulguration of bladder ulcers, neuromodulation, local injection of botulinum toxin (Botox) and injection of hydrocortisone, saline and heparin around ulcers should always be considered first. Complex surgical options available include partial cystectomy, augmentation cystoplasty and urinary diversion with or without cystectomy. However, the potential complications from these surgical procedures need to be carefully considered.

Conclusion
The clinical diagnosis of interstitial cystitis is based on identifying symptom criteria and excluding organic disease. A careful history will identify the need for diagnostic studies and treatments, depending on the nature and severity of the predominant symptoms and the extent of influencing factors. As with other chronic illnesses, a multi-component model encompassing physiologic, affective, cognitive, and behavioural approach aided by non-pharmacological and pharmacological therapy may result in the most effective outcome.

The prognosis is very variable from complete resolution of symptoms within months, a waxing and waning course, completely asymptomatic with intermittent flares, or a chronically progressive course of increasing symptoms over several years. Interstitial cystitis can and does have a significant and profound effect on women’s quality of life.

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.
2. Wein AJ, Hanno PM, et al. Interstitial cystitis: an introduction to the problem. In: Hanno PM, Staskin DR, Krane RJ, Wein AJ. (eds) Interstitial Cystitis. London: Springer, 1990; 13-15.
3. Vanga P, Arunkalaivanan AS. Painful bladder syndrome / intersti- tial cystitis and its management. In: Studd J, Tan SL, Chervenak FA (eds) Progress in Obstetrics and Gynecology. London: Elsevier, 2008; 343-357
4. Forest JB. Epidemiology and quality of life. J Reprod Medicine 2006; 51(Suppl): 227-233
5. Parsons M, Toozs-Hobson P. The investigation and management of interstitial cystitis. J Br Menopause Soc 2005; 11:132-9.
6. Leppilahti M, Sairanen J, Tammela TL et al. Finnish Interstitial Cystitis-Pelvic Pain Syndrome Study Group. Prevalence of clinically confirmed interstitial cystitis in women: a population based study in Finland. J Urol 2005; 174: 581-3
7. Keay S, Warren JW. A hypothesis for the etiology of interstitial cystitis based upon inhibition of bladder epithelial repair. Med Hypotheses 1998; 51: 79-83
8. Russel AL. Glycoaminoglycan (GAG) deficiency in protective barrier as an underlying, primary cause of ulcerative colitis, Crohn’s disease interstitial cystitis and possibly Reiter’s disease. Med Hypotheses 1999; 52:297-301.
9. Peeker R, Atanasiu L, Logadottir Y. Intercurrent autoimmune conditions in classic and non-ulcer interstitial cystitis. Scand J Urol Nephrol 2003; 37:60-3.
10. Alagiri M, Chottiner S, Ratner V, Slade D, Hanno PM. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology 1997; 49:52-7.
11. Graham E, Chai TC. Dysfunction of bladder urothelium and blad- der urothelial cells in interstitial cystitis. Curr Urol Report 2006; 7: 440-6
12. Bade J, Ishizuka O, Yoshida M. Future research needs for the definition/diagnosis of interstitial cystitis. Int J Urol 2003; 10; Suppl:S31-4.
13. Executive Committee Summary and Task Force Meeting Report. Epidemiology of Interstitial Cystitis, Maryland USA, October 2003. (www.niddk.nih.gov/fund/reports/ic/taskforcesummary.pdf).
14. Nordling J, Anjum FH, Bade JJ, Bouchelouche K, Bouchelouche P, Cervigni M, et al. Primary evaluation of patients suspected of having interstitial cystitis (IC). Eur Urol 2004; 45:662-9.
15. Goin JE, Olaleye D, Peters KM, Steinert B, Habicht K, Wynant G. Psychometric analysis of the University of Wisconsin Interstitial Cystitis Scale: implications for use in randomized clinical trials. J Urol 1998; 159:1085-90.
16. O’Leary MP, Sant GR, Fowler FJ Jr, Whitmore KE, Spolarich- Kroll J. The interstitial cystitis symptom index and problem index. Urology 1997; 49;Suppl 1:58-63.
17. Ito T, Tomoe H, Ueda T, Yoshimura N, Sant G, Hanno P. Clinical symptoms scale for interstitial cystitis for diagnosis and for following the course of the disease. Int J Urol 2003; 10; Suppl1:S24-6. doi:10.1046/j.1442-2042.10.s1.7.x
18. Ehren I, Hosseini A, Lundberg JO, Wiklund NP. Nitric oxide: a useful gas in the detection of lower urinary tract inflammation. J Urol 1999; 162:327-9.
19. Erickson DR, Xie SX, Bhavanandan VP, Wheeler MA, Hurst RE, Demers LM, et al. A comparison of multiple urine markers for interstitial cystitis. J Urol 2002; 167:2461-9.
20. Irwin PP, Takei M, Sugino Y. Summary of the Urodynamics Work shops on IC Kyoto, Japan. Int J Urol 2003; 10; Suppl 1:S19-23.
21. Jha S, Matthew P, Toozs-Hobson P. Painful bladder syndrome and interstitial cystitis. The Obstetrician and Gynaecologist 2007; 9:34- 41
22. Haq A, Donaldson PJ, Parry JR. Oral cimetidine gives effective symptom relief in painful bladder disease: a prospective, random ized, double-blind placebo-controlled trial. BJU Int 2001; 88:444-5.
23. Van Ophoven A, Pokupic S, Heinecke A, Hertle L. A prospective, randomized, placebo controlled double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol 2004; 172:533-6.
24. Nickel JC, Barkin J, Forrest J, Mosbaugh PG, Hernandez-Graulau J, Kaufman D, et al. Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis. Urology 2005; 65:654-8.
25. Morales A, Emerson L, Nickel JC. Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. Urology, 1997; 49 (Suppl): 111-113
26. Steinhoff G, Ittah B, Rowan S. The efficacy of chondroitin sulfate 0.2% in treating interstitial cystitis. Can J Urology 2002; 9:1454-8.
27. Steinhoff G, Ittah B, Rowan S. The efficacy of intravesical sterile sodium chondroitin sulfate 0.2% in potassium tested positive patients with interstitial cystitis. Adv Exp Med Biol 2003; 539:731-9.
28. Parsons CL, Housley T, Schmidt JD, Lebow D. Treatment of inter- stitial cystitis with intravesical heparin. Br J Urol 1994; 73:504-7.
29. Yamada T, Murayama T, Andoh M. Adjuvant hydrodistension under epidural anesthesia for interstitial cystitis. Int J Urol 2003; 10:463-8.
30. Higson RH, Smith JC, Whelan P. Bladder rupture: an acceptable complication of distension therapy? Br J Urol 1978; 50:529-34.

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