Interstitial cystitis/Painful bladder syndrome

Introduction

Interstitial cystitis/painful bladder syndrome (IC/PBS), a chronic disease of unknown etiology characterized by indistinct bladder pain and non-specific urinary symptoms such as urgency and frequency and pelvic pain of unknown etiology, was first described in 1887 by Skene. It was Hunner who popularized the disease with the description of characteristic bladder wall ulcers (Figure 1).¹Hunner GL. J Boston Med Surg. 1915;172:660-5.   Despite years of intensive research, no specific clinical or urinary markers, radiographic, laboratory or serologic findings, or biopsy patterns are pathognomonic for IC. IC/PBS affects predominantly women of middle age, and significantly decreases quality of life; however, as there are no characteristic symptoms or pathognomonic findings, diagnosis of IC/PBS is mainly a diagnosis of exclusion, and it is, therefore, important to rule out diseases that might have a similar clinical picture.

Definition of IC/PBS

A diagnostic criteria for enrollment in IC/PBS studies was suggested by the National Institute of Diabetes, Digestive and Diseases of the Kidney (NIDDK) in 1988,²Gillenwater JY, Wein AJ. J Urol 140: 203-206, 1988.  ^,3Hanno PM, Landis JR, Matthews-Cook Y, et al. J Urol 161: 553-557, 1999.<  ^,4Wein A, Hanno P, Gillenwater JY. Springer-Verlag, 1990.   which included urinary urgency or bladder pain, Hunner’s ulcers or glomerulations during cystoscopy or hydrodistention, and absence of other pathologies.

Additionally, it described minimum criteria regarding age, duration of symptoms, degree of frequency, and nocturia. Nevertheless, the NIDDK definition lacked something, as with the use of this definition up to 60% patients clinically diagnosed to have IC/PBS by experienced clinicians were being missed.³Hanno PM, Landis JR, Matthews-Cook Y, et al. J Urol 161: 553-557, 1999.  

This was followed by a new term being proposed by the International Continence Society (ICS) in 2002 i.e. ‘painful bladder syndrome’, defined as ‘suprapubic pain related to bladder filling, and accompanied by other symptoms for instance increased frequency (both daytime and nighttime) in absence of proven infection or other obvious pathology.’⁵Abrams P, Cardozo L, Fall M, et al. Am J Obstet Gynecol 187: 116-126, 2002.   Later, the European Society for the Study of IC/PBS (ESSIC) renamed PBS as bladder pain syndrome (BPS), and proposed using cystoscopy and hydrodistention findings for patient staging.⁶van de Merwe JP, Nordling J, Bouchelouche P, et al. Eur Urol 53: 60-67, 2008.  

Prevalence

Although IC/PBS was initially considered to be a rare condition, its prevalence has increased considerably; this increase in prevalence is accompanied with variations and might be attributed to different definitions and multiple diagnostic criteria used, and greater physician awareness. The prevalence and incidence of IC is significantly higher for women and men than previously published estimates.⁷Clemens JQ, Meenan RT, Rosetti MCO, et al. The Journal of Urology 2005;173(1): 98-102.   The prevalence of IC/PBS symptoms increases when diagnosis is based on self-report of previous IC/PBS diagnosis,⁸Jones CA, Nyberg L. Urology 1997;49: 2-9.   and is even higher when estimated by using questionnaire without clinical examination⁹Leppilahti M, Tammela TL, et al. J Urol 168: 139- 143, 2002.  . The syndrome affects women more than men (female/male ratio ranges from 5:1 to 10:1).¹⁰Moutzouris D, Vliagoftis H, Falagas ME. Nephrol Dial Transplant 2008:80-84.   Though, the median age at diagnosis is higher among women as compared to men.¹¹Curhan GC, Speizer FE, Hunter DJ, et al. J Urol 1999;161: 549-552.  ^,12Roberts RO, Bergstralh EJ, Bass SE, et al. BJU Int 2003;91: 181-185.  

Etiopathogenesis

The etiology of IC/PBS remains unknown, and is likely multifactorial. Nevertheless, even though the underlying pathophysiology of IC/PBS is not completely understood, it primarily involves urothelial permeability changes, together with mast cell activation and neurogenic inflammation¹³Sant GR, Kempuraj D, Marchand JE, et al. Urology 2007;69: 34-40.  . Deficiency in the glycosaminoglycan layer on the luminal surface of the bladder may result in increased permeability of the underlying submucosal tissues to toxic substances in the urine.¹⁴Parsons CL, Boychuk D, Jones S, et al. J Urol. 1990;143(1):139-42.   Loss of the glycosaminoglycan layer was associated with a loss of biglycan and perlecan on the luminal layer.¹⁵Hauser PJ, Dozmorov MG, Bane BL, et al. The Journal of Urology 2008; 179(2): 764-769.  

The urothelial cell barrier function is impaired due to damage to the protective bladder lining. As a result, the epithelium is penetrated by the urinary solutes, and they activate sensory nerve endings, leading to pain and inflammation.¹⁶Parsons CL. Urology 2007;69: 9-16.   Compatible with this theory, bladder epithelial cells in patients with IC/PBS are shown to produce anti-proliferative factor (APF)¹⁷Keay S, Zhang CO, Trifillis AL, et al. J Urol 1996;156: 2073-2078.   that may further contribute to impaired urothelial cell barrier. Also, in IC/PBS patients, urothelial cells fail to release prostaglandin E2 that is crucial for urothelium protection and repair.¹⁸Rastogi P, Rickard A, Dorokhov N, et al. Am J Physiol Renal Physiol 2008;294:1129-1135.  

Other abnormalities reported in IC/PBS bladder epithelium include:¹⁹Zeng Y, Wu XX, Homma Y, et al. J Urol 2007;178: 1322-1327.  ^,20Elbadawi A. Urology 1997;49:14-40.  

• Abnormal uroplakin expression assessed by reverse transcriptase polymerase chain reaction (PCR), and
• Abnormal cellular architecture on electron microscopy.

In IC/PBS pathophysiology, mast cell may also play an important role. Patients with IC/PBS have increased number of mast cells, and more than 70% of them are activated as compared to 10% in healthy controls.²¹Theoharides TC. Drugs 2007;67: 215-235.   The urine from IC/IBS patients may also exhibit characteristic presentation. Substances indicative of mast cell activation such as interleukin-6 (IL-6), tryptase and histamine are increased in the urine of IC/PBS patients.¹⁸Rastogi P, Rickard A, Dorokhov N, et al. Am J Physiol Renal Physiol 2008;294:1129-1135.   Though the urine from IC/PBS patients may have similar concentration of Tamm-Horsfall protein not different from controls, it is qualitatively different and contains less sialic acid²²Parsons CL, Stein P, Zupkas P, et al. J Urol 2007;178: 2665- 2670.  ; thus, this altered protein may be involved in IC/PBS pathogenesis. Antiproliferative factor and Tamm-Horsfall protein are novel tests that may prove to be worthwhile pending future studies.²³Seth A, Teichman JM. Curr Urol Rep. 2008;9(5):349-57.  

In addition, neurogenic upregulation is known to play a role in the chronicity of pain, urgency and frequency, and occurs both peripherally and centrally in subjects with chronic cystitis. However, it is unclear whether neural mechanisms and inflammation are the cause of IC or the result of other initiating events.²⁴Nazif O, Teichman JMH, Gebhart GF. Urology. 2007;69(4 Suppl):24-33.   This represents an exciting area of research that may lead to additional treatments and a better understanding of IC.

The purinergic pathway has been observed to be upregulated in urothelial cells from IC/PBS patients.²⁵Chai TC, Keay S. Nat Clin Pract Urol 2004;1: 85-89.  

Clinical presentation

In IC/PBS, clinical picture is variable. The syndrome often has insidious onset and remains undiagnosed for years, since all of the initial symptoms do not appear simultaneously but rather present gradually. The symptoms include pain (an essential diagnostic criterion), nocturia, urinary frequency, and urgency (Figure 2). The symptoms may be mild and intermittent in earlier course of the disease, but tend to become constant and severe over time.²⁶Driscoll A, Teichman JM. J Urol 2001;166: 2118-2120.   Pain is usually localized to the suprapubic area, and patients with IC/PBS tend to void frequently to relieve pain.²⁷Parsons CL. Clin Obstet Gynecol 2002;45: 242-249.  

Warren et al hypothesized that certain pain characteristics are sensitive criteria for diagnosing IC/PBS.²⁸Warren JW, Brown J, Tracy JK, et al. Urology 2008; 71(3):444-448.   In the Events Preceding Interstitial Cystitis (EPIC) study, pain that worsened with a certain food or drink and/or worsened with bladder filling and/or improved with urination was reported by 151 (97%) of 156 patients. These were the only 3 criteria that applied directly to the bladder, and the same 3 criteria described the pain of 262 (97%) of 270 women in the IC Database who “definitely” had IC/PBS. The triad might describe the pain of IC/PBS and contribute to a sensitive case definition.

IC/PBS patients may present with flares lasting for several days and remissions. The precipitating factors may include beverages containing biogenic amines, smoking, caffeine, stress, allergies, and sexual activity.²¹Theoharides TC. Drugs 2007;67: 215-235.  ^,29Rosenberg M, Parsons CL, Page S. Cleve Clin J Med 2005;72: 698-704.   There is exacerbation of symptoms in women during the premenstrual week. Dyspareunia is a common finding in IC/PBS patients leading to severe sexual dysfunction and poor quality of life.³⁰Nickel JC, Parsons CL, Forrest J, et al. J Sex Med 2008;5: 394-399.  

Additionally, women with IC/PBS have been observed to have significantly more hysterectomies and other pelvic surgeries than age-matched controls; most of them are done before IC/PBS diagnosis.³¹Ingber MS, Peters KM, Killinger KA, et al. Int Urogynecol J Pelvic Floor Dysfunct 2008;19: 341-345.   Nevertheless, it is not clear whether these operations were performed as a consequence of pelvic pain related to undiagnosed IC/PBS, or the chronic pelvic pain occurred as a consequence of surgery itself.

Comorbidities associated with IC/PBS

Clemens et al in a case control study found that a diagnosis of IC was associated with multiple other unexplained physical symptoms and certain psychiatric conditions.³²Clemens JQ, Meenan RT, Rosetti MCO, et al. The Journal of Urology 2008; 179(6): 2222-2225.   Additional specific conditions associated with IC were gastritis, fibromyalgia, anxiety disorder, headache, esophageal reflux, unspecified back disorder and depression. Interestingly, IC was also associated with a history of child abuse, although 96% of patients with IC did not have this diagnosis. Patients with IC/PBS have significant cognitive and psychosocial alterations compared to controls.³³Nickel JC, Tripp DA, Pontari M, et al. J Urol. 2010;183(1):167-72.  

Several systemic and autoimmune conditions such as irritable bowel syndrome and systemic lupus erythematosus are more frequent in IC/PBS patients compared with the general population.³⁴Peeker R, Atanasiu L, Logadottir Y. Scand J Urol Nephrol 2003;37:60-63.   Also, there is an increased prevalence of Sjogren disease, rheumatoid arthritis, and the presence of autoantibodies in IC/PBS patients. This provides a possible background for an autoimmune underlying pathophysiologic mechanism.³⁵Van De Merwe JP, Arendsen HJ. BJU Int 2000;85: 995-999.   IC/PBS is, thus, often considered a manifestation of a systemic disorder rather than a specific organ disorder.³⁶Clemens JQ. J Urol 2008;179: 813-814.  

Diagnosis

In absence of definitive diagnostic tests, IC/PBS remains a diagnosis of exclusion, ruling out other diseases and overlapping syndromes.

History and examination

A systematic history and physical examination is particularly significant. Medical history should include history of specific symptoms, urinary infections, pelvic surgeries, central nervous system, or autoimmune diseases. In contrast with endometriosis, IC/PBS symptoms typically worsen during the premenstrual week.³⁷Metts JF. Am Fam Physician 2001;64: 1199-1206.   Also, given the flaring nature of the IC/PBS, it may often be misdiagnosed as recurrent urinary tract infection (UTI) or prostatitis, and in such cases the resolution may correctly be attributed to antibiotic therapy, and not to the disease’s natural pattern.³⁸Rosenberg MT, Newman DK, Page SA. Cleve Clin J Med 2007;74[Suppl 3]: S54-S62.  

The Wisconsin Interstitial Cystitis Scale, initially validated in a small population, has been shown in subsequent larger studies to be valid and easy to implement, and has also been shown to correlate well with other validated IC questionnaires.³⁹Keller ML, McCarthy DO, Neider RS. Urol Clin North Am. 1994;21(1):67-71.  ^,40Goin JE, Olaleye D, Peters KM, et al. J Urol. Mar 1998;159(3):1085-90.  ^,41Sirinian E, Azevedo K, Payne CK. J Urol. Mar 2005;173(3):835-40.  

The Interstitial Cystitis Symptom and Problem Index (O’Leary-Sant Interstitial Cystitis Symptom and Problem Index) are self-administered questionnaires that were found to be valid and reliable and serve as a useful adjunct to aid in diagnosis, and have also been shown to be responsive to changes in IC symptoms.⁴²O’Leary MP, Sant GR, Fowler FJ Jr, et al. Urology. 1997;49(5A Suppl):58-63.   It may, therefore, be useful in measuring response to therapy in both clinical and research settings.⁴³Lubeck DP, Whitmore K, Sant GR, et al. Urology. 2001;57(6 Suppl 1):62-6.   However, they were not designed to be used as a screening tool.

Though there are no specific physical findings in IC/PBS patients, a careful pelvic examination is required to rule out other conditions such as vaginitis, vulvar lesions, urethral diverticula, and pelvic floor dysfunction. Also, it may show anterior vaginal wall and bladder base tenderness in women with IC/PBS. In addition, women with IC may have pelvic floor dysfunction.⁴⁴Peters KM, Carrico DJ, Kalinowski SE, et al. Urology. 2007;70(1):16-8.   A voiding diary may help in documenting voiding volume and frequency, not only for screening reasons but also for monitoring the treatment response.

Laboratory tests

Though there are no laboratory (urine or blood) tests that will identify IC/PBS, it may be vital to rule out overlapping diseases for instance urinalysis and urine culture to exclude UTI, and urine cytology in presence of hematuria, particularly in older patients with a history of smoking or with other risk factors for bladder malignancy. Severe cases of hematuria may require cystoscopic evaluation.

A number of urinary biomarkers were tested in the search for noninvasive techniques for IC/PBS diagnosis. While urine IL-6 levels were increased only in newly diagnosed patients²¹Theoharides TC. Drugs 2007;67: 215-235.  , it is still not clear whether it could be used as a diagnostic marker or as a predictor to treatment response.⁴⁵Daha LK, Lazar D, Simak R, et al. Int Urogynecol J Pelvic Floor Dysfunct 2007;18: 1449- 1452.   Keay et al suggested anti-proliferative factor as a candidate biomarker for IC/PBS diagnosis; it was shown to have increased activity in the bladders of patients with IC/PBS compared with asymptomatic controls.⁴⁶Keay S, Zhang CO, Marvel R, et al. Urology 2001;57: 104.  

Hosseini et al tested nitric oxide (NO), a nonspecific marker of inflammation, as a possible diagnostic tool. The investigators observed that NO levels in the bladder correlated with the degree of inflammation and with the response to treatment. Nevertheless, the technique had a limitation as measurement of NO levels required catheterization⁴⁷Erickson DR, Xie SX, Bhavanandan VP, et al. J Urol 2002;167:2461-2469.  ^,48Hosseini A, Ehren I, Wiklund NP. J Urol 2004;172: 2261-2265.  

Canter et al used proteomic techniques and quantitative biomarker analysis and reported that IC/PBS patients had decreased concentration of uromodulin, kininogen, and increased levels of inter-α-trypsin inhibitory heavy chain H4 in their urine.⁴⁹Canter MP, Graham CA, Heit MH, et al. Am J Obstet Gynecol 2008; 198:553e1-553e6.   However, further studies are required to investigate their use as potential biomarkers.

Besides looking for the specific diagnostic markers, a number of other procedures may be used to facilitate the diagnosis of IC/PBS (Table 1).

Treatment for IC/PBS

Symptom severity has been found to be associated with impairment in quality of life in IC/PBS patients. Managing pain and nocturia may improve the patients’ overall physical quality of life.⁵²El Khoudary SR, Talbott EO, Bromberger JT, et al. Journal of Women’s Health 2009, 18(9): 1361-1368.  

Treatment of IC/PBS suffers from lack of evidence, and therapies are largely empiric or based on case series or small studies. It may include supportive therapies (psychosocial, behavioral, physical), and specific therapies (oral treatments, and intravesical or instillation treatments), while other specific and more invasive treatments for example electric neuromodulation and reconstructive surgery are reserved for refractory cases. Other comorbid diseases that are common in IC/PBS patients (i.e., inflammatory bowel disease) should be diagnosed and treated aggressively. An algorithm may be used for effective management of IC/PBS.⁵³http://www.icsoffice.org/Publications/ICI_3/v2.pdf/chap23.pdf  

Supportive therapies

This includes general measures to alleviate symptoms or prevent exacerbations. Psychosocial support is an essential part of any chronic pain treatment. IC/PBS affects the quality of life of the affected patients; depression is not uncommon in IC/PBS patients, and may warrant a referral to the specialists if such a diagnosis is suspected.

Dietary modification involves elimination of bladder irritants, fluid regulation, and a bowel regimen. Nutraceuticals studied for the IC/PBS treatment include calcium glycerophosphate, L-arginine, mucopolysaccharides, bioflavinoids, and Chinese herbs. Bladder training is effective after pain reduction.⁵⁴Whitmore KE. Rev Urol. 2002;4 Suppl 1:S28-35.  

Certain foods, including coffee, alcohol, spicy foods, have been implicated in aggravating symptoms of IC. Factors associated with symptom exacerbation such as allergies and any specific body position should be avoided. Avoidance of possible triggering factors or timed voiding protocol leading to increased bladder capacity are typical examples of behavioral therapy that can be effective in improving symptoms of IC/PBS.⁵⁵Parsons CL, Koprowski PF. Urology 1991;37: 207-212.   Generally, if tolerated by the patient, a trial of behavioral therapy is warranted prior to proceeding to more invasive or expensive therapies.

Specific therapies

It is important to well select IC/PBS patients for treatments based on individual patient characteristics. At present, the cystoscopic evidence for the presence/absence of visible ulcers is the most common basis for stratification. The distinction is useful since visible ulcers can be fulgurated to decrease pain (Figure 4).⁵⁶Rofeim O, Hom D, Freid RM, et al. J Urol 2001; 166: 134-136.   Considering response to treatment, though there are many indicators of bladder inflammation in patients with IC/PBS (ulcers, NO, urine markers, bladder biopsy findings), it remains unclear which of these are most predictive of response to treatment.⁵⁷Erickson DR, Tomaszewski JE, Kunselman AR, et al. J Urol 2008; 179:1850-1856.   Specific therapies include: oral, intravesical treatments, and other treatments such as bladder hydraulic distension, transurethral resection of ulcers, reconstructive surgery, and neuromodulation being used predominantly in refractory cases. The cost-benefit ratio should be considered before recommending one of these invasive treatments.

Oral therapy

Medical therapy is perceived to be superior to invasive therapy in the treatment of IC, and should be considered the first line therapy for IC.⁵⁸Hill JR, Isom-Batz G, Panagopoulos G, et al. Urology. 2008;71(1):62-6.  

Pentosanpolysulfatesodium, asemi-syntheticallyproduced heparin-like macromolecular carbohydrate derivative, which chemically and structurally resembles glycosaminoglycans,⁵⁹http://www.rxlist.com/elmiron-drug.htm   is an effective oral therapy to control the symptoms of IC/ PBS with good long-term efficacy and tolerability,⁶⁰Al-Zahrani AA, Gajewski JB. Can Urol Assoc J. 2011;5(2):113-8.   and is the first- line treatment for IC/PBS.⁶¹French LM, Bhambore N. Am Fam Physician. 2011;83(10):1175-81.   The drug is chemically similar to the substance that lines the bladder, and is believed to assist in the repair or restoration of the lining tissues in the bladder.⁶²http://www.rxlist.com/interstitial_cystitis/page4.htm#tocg   It has been observed that initiation of treatment with this drug within 6 months of establishing the diagnosis of IC may be associated with greater improvement in patient symptoms and symptom bother.⁶³Nickel JC, Kaufman DM, Zhang HF, et al. Urology. 2008 Jan;71(1):57-61.  

Antispasmodic drugs

Antispasmodic bladder drugs (e.g. Flavoxate⁶⁴Barkin J. The Canadian journal of urology 2011;18(Supplement 1):8-13.  ) can help in reducing the intravesical pressure, and increase bladder capacity by antagonizing parasympathetic neuronal stimulator of the destrusor muscle. Also, they help in reducing the frequency of involuntary contractions of the bladder.⁶⁵http://www.ic-network.com/glossary/glossaryoral.html#Flavoxate.  

Flavoxate appears to have a moderate calcium antagonistic action, inhibitory effect on phosphodiesterase, and a local relaxant effect on smooth muscle.⁶⁶Yamaguchi O, Nishizawa O, Takeda M, et al. International Journal of Urology 2009;16(2):126-142.   Flavoxate has been observed empirically to have almost no adverse reactions. Several open-label or controlled studies in patients with detrusor instability, or frequency, urgency, or urge urinary incontinence have been conducted. At a dose of 600 mg or 800 mg in patients with storage symptoms, there were almost no adverse reactions, and nocturia, urgency, and bladder capacity showed a tendency to improve.

Botulinum toxin

Botulinum toxin type A is an emerging therapy for many urologic diseases associated with frequency, urgency, and urge incontinence; however, it is still considered investigational in the treatment of IC/PBS.⁶⁷Flynn MK, Webster GD, Amundsen CL. J Urol. 2004;172(6 Pt 1):2316-20.  ^,68Rajkumar GN, Conn IG. Urology. 2004;64(1):2-8.   ^,69Rapp DE, Lucioni A, Katz EE, et al. Urology. Jun 2004;63(6):1071-5.  

Sacral neurostimulation

Sacral neurostimulation continues to evolve and should be in the armamentarium available to treat voiding dysfunction.⁷⁰Kenneth M Peters. Rev Urol. 2002; 4(Suppl 1): S36-S43.   The use of sacral neuromodulation is based on the hypothesis that IC/PBS symptoms may arise from a chronic simulation and pathologic upregulation of the pelvic nerves. The technique using an implantable neuroprosthetic device (which was found to be effective in treating urgency and frequency) reported a decrease in narcotic requirements in refractory IC/PBS.⁷¹Peters KM, Carey JM, Konstandt DB. Int Urogynecol J Pelvic Floor Dysfunct 2003;14: 223-228.   However, the drawbacks of this technique include high cost, pain at the neurostimulator site, need for surgical revisions, and risk of infection. The complications rate of this technique is expected to decrease with use of less invasive technique and technical improvements of the newer devices.⁷²Oerlemans DJ, van Kerrebroeck, PE. Neurourol Urodyn 2008;27:28-33.  

Reconstructive surgery

Considering the potential complication and the risk-benefit ratio, reconstructive surgery should be reserved only for patients refractory to conservative treatment and those with classic IC/PBS; these patients are likely to benefit most.

Conclusion

IC/PBS is a chronic multifactorial disease of unclear etiology, significantly affecting quality of life, and increasing costs. The treatment course may require close follow-up of the patients as prolonged administration of medications may be needed before symptoms alleviation. It is important that the physicians keep in mind the diagnosis of IC/PBS in patients presenting with chronic urinary symptoms after excluding other more common diseases.

Pentosan polysulfate sodium therapy has been observed to significantly increase treatment satisfaction among responders.⁷³Sand PK, Kaufman DM, Evans RJ, et al. Curr Med Res Opin. 2008;24(8):2259-64.  

Flavoxate, an antispasmodic bladder drug, seems to have a moderate calcium antagonistic action, and a local relaxant effect on smooth muscle. It reduces intravesical pressure, increases bladder capacity, and help in reducing the frequency of involuntary contractions of the bladder, and is, therefore, potentially useful in alleviating the symptoms of IC/PBS.

Future prospects

Given the short duration of trials, the heterogeneity of disease, and the lack of evidence for its natural history, evaluation of treatment efficacy in IC/PBS is complicated. A lack of long-term follow-up in a disease with flares and remissions would otherwise make it impossible to attribute improvement to the intervention and not to disease fluctuation itself. Also, there should be a consensus as regards to objective standardized outcome measures to ensure that improvement is actually accomplished, and is not the result of frequent subjective changes observed in patients with chronic disease. More randomized controls are needed to develop evidence-based therapies for safe and effective interventions in patients with this chronic and debilitating disease.

References

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