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
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 "common" bladder infection (cystitis) or a UTI. 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 nocturia.^[10]

In general, symptoms are:^[11]

• Painful urination
  • Pain that is worsened with bladder filling and/or improved with urination.
  • Pain that is worsened with a certain food or drink.
  • Some patients report dysuria (burning sensation in the urethra when urinating).
• Urinary frequency (as often as every 10 minutes), urgency, and pressure in the bladder and/or pelvis.
• Some patients report nocturia (waking at night to urinate), urinary hesitancy (needing to wait for the stream to begin, often caused by pelvic floor dysfunction and tension), pain with sexual intercourse, and discomfort and difficulty driving, travelling or working.

During cystoscopy, 5-10% of IC patients are found to have Hunner's ulcers.^[12] Patients may have discomfort only in their urethra, while others struggle with pain in the entire pelvis. Interstitial cystitis patients often exhibit their symptoms in 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 suffer from other conditions that may have the same etiology as IC/BPS. These include: irritable bowel syndrome (IBS), fibromyalgia, chronic fatigue syndrome, endometriosis,^[14] vulvodynia, chemical sensitivities,^[11] allergies, Sjogren's syndrome, Systemic lupus erythematosus, and anxiety disorder.^[15] 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.^[16]

Causes

The cause of IC/BPS is currently unknown.^[9] However, several explanations have been proposed and include: 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][17][18] In addition, recent research shows that IC patients may have a substance in the urine that inhibits the growth of cells in the bladder epithelium.^[15] An infection may then predispose those patients 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 that there is a proliferation of nerve fibers present in the bladders of IC patients which is absent in the bladders of people who have not been diagnosed with IC.^[11]

Regardless of the origin, it is clear that the majority of IC/BPS patients struggle with a damaged urothelium, or bladder lining.^[19] 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 that are placed directly into the bladder via a catheter sometimes work to repair and rebuild this damaged/wounded lining, allowing for a reduction in symptoms.^[20] 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 Adherence Theory).^[21] 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 IC patients when compared to individuals without interstitial cystitis.^[22]

Numerous studies have noted the link between IC, anxiety, stress, hyperresponsiveness, and panic.^[15] Another proposed etiology for interstitial cystitis is that the body's immune system attacks the bladder.^[23] 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.^[24] Additionally, the idea has been put forward that IC is 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 patients, have been linked to the disorder.

• An antiproliferative factor secreted by the bladders of IC/BPS patients which inhibits bladder cell proliferation, thus possibly causing the missing bladder lining.^[11][15]

• PAND, at gene map locus 13q22-q32, is associated with a constellation of disorders (a "pleiotropic syndrome") including IC/BPS and other bladder and kidney problems, thyroid diseases, serious headaches/migraines, panic disorder, and mitral valve prolapse.^[15]

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^[25] 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 available symptoms.

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 Guideline also listed several discontinued treatments, including: long term oral antibiotics, intravesical Bacillus Calmette Guerin (BCG), intravesical resiniferatoxin (RTX), high pressure & 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 patients.^[8][28] However, it is unknown exactly how this procedure causes pain relief.^[29] Recent studies showing that pressure on pelvic trigger points can relieve symptoms may be connected. The relief achieved by bladder distensions is only temporary (weeks or months) and consequently, 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, a wood pulp extract, 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 that the FDA approved dosage 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 it is thought that DMSO can 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] Interstitial cystitis patients 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. Patients may be able to reduce sensitivity to trigger foods if they consume calcium glycerophosphate and/or sodium bicarbonate.^[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 patients with IC is unclear. Researchers hypothesize that integration of neural signals from pelvic organs mediates 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 milligrams 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

A 2002 review study reported that acupuncture alleviates pain associated with IC/BPS as part of multimodal treatment.^[35] While a small 1987 study showed that 11 of 14 (78%) patients had a >50% reduction in pain,^[36] a 1993 study found no beneficial effect.^[37] A 2008 review found that 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

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

This is theorized to leave the pelvic area in a sensitized condition resulting in a loop of muscle tension and heightened neurological feedback (neural wind-up). This is 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, however, 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

Surgical interventions are rarely used for IC/BPS. Surgical intervention is very unpredictable for IC/BPS, 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] PTNS stimulators have also been used, with varying degrees of success.^[44] Percutaneous sacral nerve root stimulation (PNS) 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

• Chronic prostatitis/chronic pelvic pain syndrome - women have vestigial prostate glands that may cause IC/BPS-like symptoms. Men with IC/BPS may have prostatitis, and vice versa.
• Overactive bladder
• Pelvic Myoneuropathy - a new explanation for painful bladder.
• Quercetin - alternative medicine- a flavonoid that has anti-inflammatory properties, used to treat IC/BPS with some success.
• Trigger Points - a key to myofascial pain syndrome.

References

External links

• Interstitial cystitis on the Open Directory Project
• National Library of Medicine: The Historical Origins of Interstitial
• The National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC)
• Clinical guidelines for interstitial cystitis and hypersensitive bladder syndrome (International Journal of Urology)
• European Urology

v t e Urinary system Pathology Urologic disease / Uropathy (N00–N39, 580–599) Abdominal Nephropathy/ (nephritis+ nephrosis) Glomerulopathy/ glomerulitis/ (glomerulonephritis+ glomerulonephrosis) Primarily nephrotic Non-proliferative Minimal change Focal segmental Membranous Proliferative Mesangial proliferative Endocapillary proliferative Membranoproliferative/mesangiocapillary By condition Diabetic Amyloidosis Primarily nephritic, RPG Type I RPG/Type II hypersensitivity Goodpasture's syndrome Type II RPG/Type III hypersensitivity Post-streptococcal Lupus DPN IgA/Berger's Type III RPG/Pauci-immune Granulomatosis with polyangiitis Microscopic polyangiitis Churg–Strauss syndrome Tubulopathy/ tubulitis Proximal RTA RTA 2 Fanconi syndrome Thick ascending Bartter syndrome Distal convoluted Gitelman syndrome Collecting duct Liddle's syndrome RTA RTA 1 Diabetes insipidus Nephrogenic Renal papilla Renal papillary necrosis Major calyx/pelvis Hydronephrosis Pyonephrosis Reflux nephropathy Any/all Acute tubular necrosis Interstitium Interstitial nephritis Pyelonephritis Danubian endemic familial nephropathy Any/all General syndromes Renal failure Acute renal failure Chronic kidney disease Uremic pericarditis Uremia Vascular Renal artery stenosis Renal ischemia Hypertensive nephropathy Renovascular hypertension Renal cortical necrosis Other Analgesic nephropathy Renal osteodystrophy Nephroptosis Abderhalden–Kaufmann–Lignac syndrome Ureter Ureteritis Ureterocele Megaureter Pelvic Bladder Cystitis Interstitial cystitis Hunner's ulcer Trigonitis Hemorrhagic cystitis Neurogenic bladder dysfunction Bladder sphincter dyssynergia Vesicointestinal fistula Vesicoureteral reflux Urethra Urethritis Non-gonococcal urethritis Urethral syndrome Urethral stricture/Meatal stenosis Urethral caruncle Any/all Obstructive uropathy Urinary tract infection Retroperitoneal fibrosis Urolithiasis Bladder stone Kidney stone Renal colic Malakoplakia Urinary incontinence Stress Urge Overflow M: URI anat/phys/devp/cell noco/acba/cong/tumr, sysi/epon, urte proc/itvp, drug (G4B), blte, urte