Interstitial cystitis

Bladder pain syndrome/interstitial cystitis
Classification and external resources
ICD-10 N30.1
ICD-9 595.1
DiseasesDB 30832
MedlinePlus 000477
eMedicine med/2866
Patient UK Interstitial cystitis
MeSH D018856

Interstitial cystitis,[1] or bladder pain syndrome (also IC/BPS), is a chronic inflammatory condition of the submucosal and muscular layers of the bladder.[2] The cause of IC/BPS is currently unknown and the condition is regarded as a diagnosis of exclusion. IC/BPS may be associated with urinary urgency, urinary frequency, waking at night to urinate (nocturia), and sterile urine cultures.[3][4] Those with interstitial cystitis may have symptoms that overlap with other urinary bladder disorders such as: urinary tract infection (UTI), overactive bladder, urethritis, urethral syndrome, and prostatitis.[5] IC/BPS can result in a quality of life comparable to that of a patient with rheumatoid arthritis, chronic cancer pain, or a patient on kidney dialysis.[6][7]

Signs and symptoms

The symptoms of IC/BPS are often misdiagnosed as a urinary tract infection. However, IC/BPS has not been shown to be caused by a bacterial infection and antibiotics are an ineffective treatment. The symptoms of IC/BPS may also initially be attributed to prostatitis and epididymitis (in men) and endometriosis and uterine fibroids (in women).

The most common symptoms of IC/BPS are suprapubic pain,[8] urinary frequency, painful sexual intercourse,[9] and waking up from sleep to urinate.[10]

In general, symptoms may include[11] painful urination described as a burning sensation in the urethra during urination, pelvic pain that is worsened with the consumption of certain foods or drinks, urinary urgency, and pressure in the bladder or pelvis. Other frequently described symptoms are urinary hesitancy (needing to wait for the urinary stream to begin, often caused by pelvic floor dysfunction and tension), and discomfort and difficulty driving, working, or traveling. Pelvic pain experienced by those with IC typically worsens with filling of the urinary bladder and may improve with urination.

During cystoscopy, 5–10% of people with IC are found to have Hunner's ulcers.[12] A person with IC may have discomfort only in the urethra, while another might struggle with pain in the entire pelvis. Interstitial cystitis symptoms usually fall into one of two patterns: significant suprapubic pain with little frequency or a lesser amount of suprapubic pain but with increased urinary frequency.[13]

Association with other conditions

Some people with IC/BPS have been diagnosed with other conditions such as irritable bowel syndrome (IBS), fibromyalgia, chronic fatigue syndrome, allergies, Sjogren's syndrome, which raises the possibility that interstitial cystitis may be caused by mechanisms that cause these other conditions.[14] In addition, men with IC/PBS are frequently diagnosed as having chronic nonbacterial prostatitis, and there is an extensive overlap of symptoms and treatment between the two conditions, leading researchers to posit that the conditions may share the same etiology and pathology.[15]

Causes

The cause of IC/BPS is currently unknown.[9] However, several explanations have been proposed and include the following: autoimmune theory, nerve theory, mast cell theory, leaky lining theory, infection theory, and a theory of production of a toxic substance in the urine. Other suggested etiological causes are neurologic, allergic, genetic, and stress-psychological.[12][16][17] In addition, recent research shows that those with IC may have a substance in the urine that inhibits the growth of cells in the bladder epithelium.[14] An infection may then predispose those people to develop IC. Current evidence from clinical and laboratory studies confirms that mast cells play a central role in IC/PBS possibly due to their ability to release histamine and cause pain, swelling, scarring, and interfere with healing.[4] Research has shown a proliferation of nerve fibers is present in the bladders of people with IC which is absent in the bladders of people who have not been diagnosed with IC.[11]

Regardless of the origin, the majority of people with IC/BPS struggle with a damaged urothelium, or bladder lining.[18] When the surface glycosaminoglycan (GAG) layer is damaged (via a urinary tract infection (UTI), excessive consumption of coffee or sodas, traumatic injury, etc.), urinary chemicals can "leak" into surrounding tissues, causing pain, inflammation, and urinary symptoms. Oral medications like pentosan polysulfate and medications placed directly into the bladder via a catheter sometimes work to repair and rebuild this damaged/wounded lining, allowing for a reduction in symptoms.[19] Most literature supports the belief that IC's symptoms are associated with a defect in the bladder epithelium lining, allowing irritating substances in the urine to penetrate into the bladder—essentially, a breakdown of the bladder lining (also known as the adherence theory).[20] Deficiency in this glycosaminoglycan layer on the surface of the bladder results in increased permeability of the underlying submucosal tissues.[11]

GP51 has been identified as a possible urinary biomarker for IC with significant variations in GP51 levels in those with IC when compared to individuals without interstitial cystitis.[21]

Numerous studies have noted the link between IC, anxiety, stress, hyper-responsiveness, and panic.[14] Another proposed etiology for interstitial cystitis is that the body's immune system attacks the bladder.[22] Biopsies on the bladder walls of people with IC usually contain mast cells. Mast cells containing histamine packets gather when an allergic reaction is occurring. The body identifies the bladder wall as a foreign agent, and the histamine packets burst open and attack. The body attacks itself, which is the basis of autoimmune disorders.[23] Additionally, IC may be triggered by an unknown toxin or stimulus which causes nerves in the bladder wall to fire uncontrollably. When they fire, they release substances called neuropeptides that induce a cascade of reactions that cause pain in the bladder wall.[4]

Genes

Some genetic subtypes, in some people, have been linked to the disorder.

Diagnosis

A diagnosis of IC/BPS is one of exclusion, as well as a review of clinical symptoms.[8] The AUA Guidelines recommend starting with a careful patient history, physical examination and laboratory tests to assess and document symptoms of IC, as well as other potential disorders.

The KCl test, also known as the potassium sensitivity test, is no longer recommended. The test uses a mild potassium solution to evaluate the integrity of the bladder wall.[11] Though the latter is not specific for IC/BPS, it has been determined to be helpful in predicting the use of compounds, such as pentosan polysulphate, which are designed to help repair the GAG layer.

For complicated cases, the use of hydrodistention with cystoscopy may be helpful. Researchers, however, determined that this visual examination of the bladder wall after stretching the bladder was not specific for IC/BPS[24] and that the test, itself, can contribute to the development of small glomerulations (petechial hemorrhages) often found in IC/BPS. Thus, a diagnosis of IC/BPS is one of exclusion, as well as a review of clinical symptoms.

In 2006, the ESSIC society proposed more rigorous and demanding diagnostic methods with specific classification criteria so that it cannot be confused with other, similar conditions. Specifically, they require that a patient must have pain associated with the bladder, accompanied by one other urinary symptom. Thus, a patient with just frequency or urgency would be excluded from a diagnosis. Secondly, they strongly encourage the exclusion of confusable diseases through an extensive and expensive series of tests including (A) a medical history and physical exam, (B) a dipstick urinalysis, various urine cultures, and a serum PSA in men over 40, (C) flowmetry and post-void residual urine volume by ultrasound scanning and (D) cystoscopy. A diagnosis of IC/BPS would be confirmed with a hydrodistention during cystoscopy with biopsy.

They also propose a ranking system based upon the physical findings in the bladder.[11] Patients would receive a numeric and letter based score based upon the severity of their disease as found during the hydrodistention. A score of 1–3 would relate to the severity of the disease and a rating of A–C represents biopsy findings. Thus, a patient with 1A would have very mild symptoms and disease while a patient with 3C would have the worst possible symptoms. Widely recognized scoring systems such as the O'Leary Sant symptom and problem score have emerged to evaluate the severity of IC symptoms such as pain and urinary symptoms.[25]

In 2009, Japanese researchers identified a urinary marker called phenylacetylglutamine that could be used for early diagnosis.[26]

Treatment

AUA treatment guidelines

In 2011, the American Urological Association released the first consensus-based guideline for the diagnosis and treatment of IC in the USA.[27]

The AUA treatment guidelines include a treatment protocol ranging from conservative treatments to more invasive interventions:

  1. First-line treatments — patient education, self care (diet modification), stress management
  2. Second-line treatments — physical therapy, oral medications (amitryptiline, cimetidine or hydroxyzine, pentosan polysulfate), bladder instillations (DMSO, heparin, or lidocaine)
  3. Third-line treatments — treatment of Hunner's ulcers (laser, fulguration or triamcinolone injection), hydrodistention (low pressure, short duration)
  4. Fourth-line treatments — neuromodulation (sacral or pudendal nerve)
  5. Fifth-line treatments — cyclosporine A, botulinum toxin (BTX-A)
  6. Sixth-line treatments — surgical intervention (urinary diversion, augmentation, cystectomy)

The AUA guidelines also listed several discontinued treatments, including: long-term oral antibiotics, intravesical bacillus Calmette Guerin, intravesical resiniferatoxin), high-pressure and long-duration hydrodistention, and systemic glucocorticoids.

Bladder distension

Bladder distension while under general anesthesia, also known as hydrodistention (a procedure which stretches the bladder capacity), has shown some success in reducing urinary frequency and giving short-term pain relief to those with IC.[8][28] However, it is unknown exactly how this procedure causes pain relief.[29] Recent studies show pressure on pelvic trigger points can relieve symptoms. The relief achieved by bladder distensions is only temporary (weeks or months), so is not viable as a long-term treatment for IC/BPS. The proportion of IC/BPS patients who experience relief from hydrodistention is currently unknown and evidence for this modality is limited by a lack of properly controlled studies.[8] Bladder rupture and sepsis may be associated with prolonged, high-pressure hydrodistention.[8]

Bladder Instillations

Bladder instillation of medication is one of the main forms of treatment of interstitial cystitis, but evidence for its effectiveness is currently limited. Advantages of this treatment approach include direct contact of the medication with the bladder and low systemic side effects due to poor absorption of the medication.[8] Single medications or a mixture of medications are commonly used in bladder instillation preparations. DMSO is the only approved bladder instillation for IC/BPS yet it is much less frequently used in urology clinics.[28]

Research studies presented at recent conferences of the American Urological Association by C. Subah Packer have demonstrated the FDA-approved dose of a 50% solution of DMSO had the potential to create irreversible muscle contraction. However, a lesser solution of 25% was found to be reversible. Long-term use of DMSO is questionable, as its mechanism of action is not fully understood though DMSO is thought to inhibit mast cells and may have anti-inflammatory, muscle-relaxing, and analgesic effects.[8][11] Other agents used for bladder instillations to treat interstitial cystitis include: heparin, lidocaine, chondroitin sulfate, hyaluronic acid, pentosan polysulfate, oxybutynin, and botulinum toxin A. Preliminary evidence suggests these agents are efficacious in reducing symptoms of interstitial cystitis, but further study with larger, randomized, controlled clinical trials is needed.[8]

Diet

Diet modification is often recommended as a first-line method of self-treatment for interstitial cystitis, though rigorous controlled studies examining the impact diet has on interstitial cystitis signs and symptoms are currently lacking.[8] Individuals with interstitial cystitis often experience an increase in symptoms when they consume certain foods and beverages. Avoidance of these potential trigger foods and beverages such as caffeine-containing beverages including coffee, tea, and soda, alcoholic beverages, chocolate, citrus fruits, hot peppers, and artificial sweeteners may be helpful in alleviating symptoms.[9][11] Diet triggers vary between individuals with IC;[8] the best way for a person to discover his or her own triggers is to use an elimination diet. Sensitivity to trigger foods may be reduced if calcium glycerophosphate and/or sodium bicarbonate is consumed.[30] The foundation of therapy is a modification of diet to help patients avoid those foods which can further irritate the damaged bladder wall.

The mechanism by which dietary modification benefits people with IC is unclear. Integration of neural signals from pelvic organs may mediate the effects of diet on symptoms of IC.[31]

Medications

The antihistamine hydroxyzine failed to demonstrate superiority over placebo in treatment of IC patients in a randomized, controlled, clinical trial.[8] Amitriptyline has been shown to be effective in reducing symptoms such as chronic pelvic pain and nocturia[8] in many patients with IC/BPS with a median dose of 75 mg daily.[11] In one study, the antidepressant duloxetine was found to be ineffective as a treatment,[32] although a patent exists for use of duloxetine in the context of IC, and is known to relieve neuropathic pain. The calcineurin inhibitor cyclosporine A has been studied as a treatment for interstitial cystitis due to its immunosuppressive properties. A prospective randomized study found cyclosporine A to be more effective at treating IC symptoms than pentosan polysulfate, but also had more adverse effects.[8]

Oral pentosan polysulfate is believed to repair the protective glycosaminoglycan coating of the bladder, but studies have encountered mixed results when attempting to determine if the effect is statistically significant compared to placebo.[8][33][34]

Pain control therapies

Acupuncture alleviates pain associated with IC/BPS as part of multimodal treatment.[35] While a small study showed 11 of 14 (78%) patients had a >50% reduction in pain,[36] another study found no beneficial effect.[37] Despite a scarcity of controlled studies on alternative medicine and IC/BPS, "rather good results have been obtained" when acupuncture is combined with other treatments.[38] Biofeedback, a relaxation technique aimed at helping people control functions of the autonomic nervous system, has shown some benefit in controlling pain associated with IC/BPS as part of a multimodal approach that may also include medication or hydrodistention of the bladder.[39][40]

Pelvic floor treatments

Urologic pelvic pain syndromes, such as IC/BPS and CP/CPPS, are characterized by pelvic muscle tenderness, and symptoms may be reduced with pelvic myofascial physical therapy.[41]

This may leave the pelvic area in a sensitized condition, resulting in a loop of muscle tension and heightened neurological feedback (neural wind-up), a form of myofascial pain syndrome. Current protocols, such as the Wise–Anderson Protocol, largely focus on stretches to release overtensed muscles in the pelvic or anal area (commonly referred to as trigger points), physical therapy to the area, and progressive relaxation therapy to reduce causative stress.[41]

Pelvic floor dysfunction is a fairly new area of specialty for physical therapists worldwide. The goal of therapy is to relax and lengthen the pelvic floor muscles, rather than to tighten and/or strengthen them as is the goal of therapy for patients with urinary incontinence. Thus, traditional exercises such as Kegel exercises, can be helpful as they strengthen the muscles, but they can provoke pain and additional muscle tension. A specially trained physical therapist can provide direct, hands on evaluation of the muscles, both externally and internally.

Surgery

Surgery is rarely used for IC/BPS. Surgical intervention is very unpredictable, and is considered a treatment of last resort for severe refractory cases of interstitial cystitis.[28] Some patients who opt for surgical intervention continue to experience pain after surgery. Typical surgical interventions for refractory cases of IC/BPS include: bladder augmentation, urinary diversion, transurethral fulguration and resection of ulcers, and bladder removal (cystectomy).[8][28]

Neuromodulation can be successful in treating IC/BPS symptoms, including pain.[42] One electronic pain-killing option is TENS.[42][43] Percutaneous tibial nerve stimulation stimulators have also been used, with varying degrees of success.[44] Percutaneous sacral nerve root stimulation was able to produce statistically significant improvements in several parameters, including pain.[41]

Prognosis

IC/BPS has a profound impact on quality of life.[4][8] A 2007 Finnish epidemiologic study showed that two-thirds of women at moderate to high risk of having interstitial cystitis reported impairment in their quality of life and 35% of IC patients reported an impact on their sexual life.[8] A 2012 survey showed that among a group of adult women with symptoms of interstitial cystitis, 11% reported suicidal thoughts in the past two weeks.[45] Other research has shown that the impact of IC/BPS on quality of life is severe[11] and may be comparable to the quality of life experienced in endstage renal disease or rheumatoid arthritis.[6][46]

International recognition of interstitial cystitis has grown and international urology conferences to address the heterogeneity in diagnostic criteria have recently been held.[47] IC/PBS is now recognized with an official disability code in the United States of America.[48]

Epidemiology

IC/BPS affects men and women of all cultures, socioeconomic backgrounds, and ages. Although the disease was previously believed to be a condition of menopausal women, growing numbers of men and women are being diagnosed in their twenties and younger. IC/BPS is not a rare condition.[49] Early research suggested that IC/BPS prevalence ranged from 1 in 100,000 to 5.1 in 1,000 of the general population. In recent years, the scientific community has achieved a much deeper understanding of the epidemiology of interstitial cystitis. Recent studies[50][51] have revealed that between 2.7 and 6.53 million women in the USA have symptoms of IC and up to 12% of women may have early symptoms of IC/BPS. Further study has estimated that the condition is far more prevalent in men than previously thought ranging from 1.8 to 4.2 million men having symptoms of interstitial cystitis.

History

Philadelphia surgeon Joseph Parrish published the earliest record of interstitial cystitis in 1836 describing three cases of severe lower urinary tract symptoms without the presence of a bladder stone.[4] The term "interstitial cystitis" was coined by Dr. Alexander Skene in 1887 to describe the disease.[11] In 2002, the United States amended the Social Security Act to include interstitial cystitis as a disability. The first guideline for diagnosis and treatment of interstitial cystitis is released by a Japanese research team in 2009.[52] The American Urological Association released the first American clinical practice guideline for diagnosing and treating IC/BPS in 2011.

Characterization

Originally called interstitial cystitis, this disorder was renamed to interstitial cystitis/bladder pain syndrome in the 2002–2010 timeframe. In 2007, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) began using the umbrella term Urologic Chronic Pelvic Pain Syndromes (UCPPS) to refer to pain syndromes associated with the bladder (i.e., interstitial cystitis/bladder pain syndrome, IC/BPS) and the prostate gland (i.e., Chronic prostatitis/chronic pelvic pain syndrome).[53]

In 2008, terms currently in use in addition to IC/BPS include painful bladder syndrome, bladder pain syndrome and hypersensitive bladder syndrome, alone and in a variety of combinations. These different terms are being used in different parts of the world. The term "interstitial cystitis" is the primary term used in ICD-10 and MeSH. The condition is officially recognized as a disability in the United States.[7][54]

See also

References

  1. ↑ /ˌɪntərˈstɪʃəl sɪˈstaɪtɨs/ IN-tər-STISH-əl si-STY-tis
  2. ↑ Vesela, R; Aronsson, P; Andersson, M; Wsol, V; Tobin, G (2012). "The potential of non-adrenergic, non-cholinergic targets in the treatment of interstitial cystitis/painful bladder syndrome.". Journal of Physiology and Pharmacology 63 (3): 209–216. PMID 22791634.
  3. ↑ Vij, M; Srikrishna, S; Cardozo, L (2012). "Interstitial cystitis: diagnosis and management". European Journal of obstetrics, gynecology, and reproductive biology 161 (1): 1–7. doi:10.1016/j.ejogrb.2011.12.014. PMID 22310942.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Persu, C; Cauni, V; Gutue, S; Blaj, I; Jinga, V; Geavlete, P (2010). "From interstitial cystitis to chronic pelvic pain". Journal of Medicine and Life 3 (2): 167–174. PMC 3019050. PMID 20968203.
  5. ↑ Bogart, LM; Berry, SH; Clemens, JQ (2007). "Symptoms of interstitial cystitis, painful bladder syndrome and similar diseases in women: a systematic review". The Journal of Urology 177 (2): 450–456. doi:10.1016/j.juro.2006.09.032. PMID 17222607.
  6. ↑ 6.0 6.1 "American Urological Association Guideline: Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome [January 2011]" (PDF). American Urological Association. Retrieved 1 April 2011.
  7. ↑ 7.0 7.1 "Harvard Medical School Family Health Guide: Treating interstitial cystitis". Harvard Medical School. Retrieved 1 April 2011.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10 8.11 8.12 8.13 8.14 8.15 8.16 Hsieh, CH; Chang, WC; Huang, MC; Su, TH; Li, YT; Chiang, HS (December 2012). "Treatment of interstitial cystitis in women". Taiwan Journal of Obstetrics & Gynecology 51 (4): 526–532. doi:10.1016/j.tjog.2012.10.002. PMID 23276554.
  9. ↑ 9.0 9.1 9.2 Pubmed Health (2012). "Interstitial Cystitis". U.S. National Library of Medicine. Retrieved 1 October 2012.
  10. ↑ Ustinova, EE; Fraser, MO; Pezzone, MA (2011). "Cross-Talk and Sensitization of Bladder Afferent Nerves". Neurourology Urodynamics 29 (1): 77–81. doi:10.1002/nau.20817. PMC 2805190. PMID 20025032.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 11.9 11.10 Moutzouris, DA; Falagas, ME (2009). "Interstitial Cystitis: An Unsolved Enigma". Clinical Journal of the American Society of Nephrology 4 (11): 1844–1857. doi:10.2215/CJN.02000309. PMID 19808225.
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  25. ↑ Tyagi P, Kashyap MP, Kawamorita N, Yoshizawa T, Chancellor M, Yoshimura N (January 2014). "Intravesical liposome and antisense treatment for detrusor overactivity and interstitial cystitis/painful bladder syndrome". ISRN Pharmacol 2014 (601653). doi:10.1155/2014/601653. PMC 3914518. PMID 24527221.
  26. ↑ Fukui, Yousuke; Kato, Masao; Inoue, Yohji; Matsubara, Akio; Itoh, Kohji (2009). "A metabonomic approach identifies human urinary phenylacetylglutamine as a novel marker of interstitial cystitis". Journal of Chromatography B 877 (30): 3806–12. doi:10.1016/j.jchromb.2009.09.025. PMID 19815468.
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  28. ↑ 28.0 28.1 28.2 28.3 "Treatments and drugs". Mayo Clinic. 2011. Retrieved 1 October 2012.
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  32. ↑ Papandreou, Christos; Skapinakis, Petros; Giannakis, Dimitrios; Sofikitis, Nikolaos; Mavreas, Venetsanos (2009). "Antidepressant Drugs for Chronic Urological Pelvic Pain: an Evidence-Based Review". Advances in Urology 2009: 1. doi:10.1155/2009/797031. PMC 2821755. PMID 20169141.
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  38. ↑ Binder, I.; Rossbach, G.; Ophoven, A. van (2008). "Die Komplexität chronischer Beckenschmerzen am Beispiel der Interstitiellen Zystitis". Aktuelle Urologie 39 (4): 289–97. doi:10.1055/s-2008-1038199. PMID 18663671.
  39. ↑ Hsieh, Ching-Hung; Chang, Shao-Tung; Hsieh, Chia-Jung; Hsu, Chun-Sen; Kuo, Tsung-Cheng; Chang, Hui-Chin; Lin, Yi-Hui (2008). "Treatment of interstitial cystitis with hydrodistention and bladder training". International Urogynecology Journal 19 (10): 1379–84. doi:10.1007/s00192-008-0640-9. PMID 18496634.
  40. ↑ Dell, JR; Parsons, CL (2004). "Multimodal therapy for interstitial cystitis". The Journal of reproductive medicine 49 (3 Suppl): 243–52. PMID 15088863.
  41. ↑ 41.0 41.1 41.2 Anderson, R; Wise, D; Nathanson, BH (2011). "Safety and effectiveness of an internal pelvic myofascial trigger point wand for urologic chronic pelvic pain syndrome". Clin J Pain 27 (9): 764–8. doi:10.1016/j.gtc.2008.06.002. PMC 2676775. PMID 18794003.
  42. ↑ 42.0 42.1 Fariello, JY; Whitmore, K (2010). "Sacral neuromodulation for IC/PBS, chronic pelvic pain, and sexual dysfunction.". International Urogynecology Journal 21 (12): 1553–1558. doi:10.1007/s00192-010-1281-3. PMID 20972541.
  43. ↑ Hunter, C; Dave, N; Diwan, S; Deer, T (January 2013). "Neuromodulation of Pelvic Visceral Pain: Review of the literature and Case Series of Potential Novel Targets for Treatment". Pain Practice 13 (1): 3–17. doi:10.1111/j.1533-2500.2012.00558.x. PMID 22521096.
  44. ↑ Zhao, J; Bai, J; Zhou, Y; Qi, G; Du, L (2008). "Posterior Tibial Nerve Stimulation Twice a Week in Patients with Interstitial Cystitis". Urology 71 (6): 1080–4. doi:10.1016/j.urology.2008.01.018. PMID 18372023.
  45. ↑ Hepner, Kimberly A.; Watkins, Katherine E.; Elliott, Marc; Clemens, J. Quentin; Hilton, Lara; Berry, Sandra H. (June 2012). "Suicidal ideation among patients with bladder pain syndrome/interstitial cystitis". Urology 80 (2): 280–285. doi:10.1016/j.urology.2011.12.053. PMC 3411912. PMID 22658505. Retrieved 16 May 2013.
  46. ↑ Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Ho N, Koziol J, Parsons CL. Epidemiology of Interstitial Cystitis, in G. Sant (Ed.), Interstitial Cystitis. Philadelphia: Lippincott-Raven Publishers, 1997; 9–15.
  47. ↑ Nickel, JC (2004). "Interstitial Cystitis:The Paradigm Shifts". Reviews in Urology 6 (4): 200–202. PMC 1472838. PMID 16985602.
  48. ↑ Rosenberg, Matt T.; Diane K. Newman; Shari E. Page (May 2007). "Interstitial cystitis/painful bladder syndrome: Symptom recognition is key to early identification, treatment" (PDF). Cleveland Clinic Journal of Medicine 74 (3): S54–62. doi:10.3949/ccjm.74.Suppl_3.S54. PMID 17546832. Retrieved 1 April 2011.
  49. ↑ Robert M. Moldwin (1 October 2000). The Interstitial Cystitis Survival Guide: Your Guide to the Latest Treatment Options and Coping Strategies. New Harbinger Publications. ISBN 978-1-57224-210-4. Retrieved 23 November 2012.
  50. ↑ Berry, SH; Elliott, MN; Suttorp, M; Bogart, LM; Stoto, MA (2011). "Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States". Journal of Urology 186 (2): 540–544. doi:10.1016/j.juro.2011.03.132. PMC 3513327. PMID 21683389.
  51. ↑ Rosenberg, MT; Newman, DK; Page, SA (2007). "Interstitial cystitis/painful bladder syndrome: symptom recognition is key to early identification, treatment". Cleveland Clinic journal of medicine. 74 Suppl 3: S54–62. doi:10.3949/ccjm.74.Suppl_3.S54. PMID 17546832.
  52. ↑ Homma, Y.; Ueda T; Ito T; Takei M; Tomoe H. (Jan 2009). "Japanese guideline for diagnosis and treatment of interstitial cystitis". International Journal of Urology 16 (1): 4–16. doi:10.1111/j.1442-2042.2008.02208.x. PMID 19120522.
  53. ↑ "Multi-disciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network". NIDDK. 2007. Retrieved 11 January 2008.
  54. ↑ "Policy Interpretation Ruling Titles II and XVI: Evaluation of Interstitial Cystitis". Social Security Administration. Retrieved 16 October 2012.

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