Interstitial cystitis

Interstitial cystitis or Bladder pain syndrome (commonly abbreviated to "IC/BPS") is a chronic, oftentimes severely debilitating disease of the urinary bladder. Of unknown cause, it is characterized by: pain associated with the bladder, pain associated with urination (dysuria), urinary frequency (as often as every 10 minutes), urgency, and/or pressure in the bladder and/or pelvis.

The disease has a profound impact on quality of life. A Harvard University study concluded, "the impact of interstitial cystitis on quality of life is severe and debilitating". A Harvard Medical School guide states that the quality of life of interstitial cystitis patients resembles that of a person on kidney dialysis or suffering from chronic cancer pain. The condition is officially recognized as a disability.

It is not unusual for patients to have been misdiagnosed with a variety of other conditions, including: overactive bladder, urethritis, urethral syndrome, trigonitis, prostatitis and other generic terms used to describe frequency/urgency symptoms in the urinary tract.

IC/BPS affects men and women of all cultures, socioeconomic backgrounds, and ages. Although the disease previously was 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, however IC/BPS is more common in women than in men. Early research suggested that IC/BPS prevalence ranged from 1 in 100,000 to 5.1 in 1,000 of the general population. In 2009, new research (now known as the RAND study) revealed that in the U.S alone, between 3 and 8 million people have interstitial cystitis. Up to 12% of women may have early symptoms of IC/BPS.

Nomenclature
Originally called interstitial cystitis Pronounced (in·ter·sti·tial/ˌɪntərˈstɪʃəl/ [in-ter-stish-uhl] sĭ-stī'tĭs), is the name for this disorder changed to interstitial cystitis/bladder pain syndrome in the period 2002-2010. 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).

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.

Causes
The cause of IC/BPS is unknown, though several theories have been put forward (these 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 theories are neurologic, allergic, genetic and stress-psychological.    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.  An infection may then predispose those patients to get IC.

Regardless of the origin, it is clear that the majority of IC/BPS patients struggle with a damaged urothelium, or bladder lining. 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.

Autoimmune
The body's immune system attacks the bladder. Biopsies on the bladder walls of people with IC usually contain mast cells. Mast cells gather when an allergic reaction is occurring. They contain histamine packets. 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.

Leaky Bladder Lining
Most literature supports the belief that IC's symptoms are associated with a defect in the bladder epithelium lining allows irritating substances in the urine to penetrate into the bladder — essentially, a breakdown of the bladder lining (also known as Adherence Theory). Deficiency in this glycosaminoglycan layer on the surface of the bladder results in increased permeability of the underlying submucosal tissues.

GP 51 is a urinary glycoprotein that functions as a protective barrier to the bladder wall. A study evaluated urinary GP 51 levels in patients with and without interstitial cystitis and found that these levels are significantly reduced in patients with the disease.

Nerve Damage [Neurological Theory]
Nerves in the bladder wall fire uncontrollably, altering other blood vessels in the area and preventing oxygen from getting to the bladder wall. The severe pain is because the neurological response becomes faulty.

Mast Cells
Mast cells were once thought to be responsible for allergic reactions. Mast cells release histamine. Histamine causes pain, swelling, scarring and prevents healing. Mast cells have in some studies been shown to be critically important in interstitial cystitis.

Current evidence from clinical and laboratory studies conﬁrms that mast cells play a central role in IC/PBS.

Research has shown that there is proliferation of nerve fibers in the bladders of IC patients that doesn’t exist in the bladders of people who have not been diagnosed with IC.

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.


 * 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.

Toxic Urine
Recently, theories have developed related to the production of a toxic substance in the urine. Scientists seeking a diagnostic test have begun to identify substances unique to the urine of interstitial cystitis patients. They have also found that certain factors required for healthy cell growth appear to be missing from the urine, a discovery that could lead to a new therapy.

Stress
In murine (rat) models, stress can produce inflammation in the bladder. Chronic psychological stress significantly enhanced bladder nociceptive responses only in high-anxiety rats supports a critical role of genetics, stress and anxiety as exacerbating factors in IC and other chronic pelvic pain conditions. Numerous studies have noted the link between IC, anxiety, stress, hyperresponsiveness, and panic.

The American Urological Association, however, states strongly that there is no evidence that stress makes a person get IC in the first place. However, the association says, it is well known that if a person has IC, physical or mental stress can make the symptoms worse.

The presence of endometriosis has a strong association with typical IC findings on cystoscopy including glomerulations, ulcers, and reduced bladder capacity.

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 the mis-prescribed treatment of antibiotics is ineffective. 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 symptom of IC/BPS is pain, which is found in 100% of patients, frequency (82% of patients) and nocturia (62%).

In general, symptoms are:


 * 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 waking at night to urinate, hesitancy (needing to wait for the stream to begin), pain with sexual intercourse, and discomfort and difficulty driving, travelling or working.

During cystoscopy, 5 to 10% of patients are found to have Hunner's ulcers. Far more patients may experience a very mild form of IC/BPS, in which they have no visible wounds in their bladder, yet struggle with symptoms of pain, frequency and/or urgency. Still other patients may have discomfort only in their urethra, while others struggle with pain in the entire pelvis.

Patients may experience nocturia, pelvic floor dysfunction and tension (thus making it difficult to start their urine stream), pain with sexual intercourse, and discomfort and difficulty driving, traveling or working.

For the most part, people with interstitial cystitis will either have lots of pain and very little frequency or they'll have lots of frequency and very little pain.

Diagnosis
Diagnosis has been greatly simplified in recent years with the development of two new methodologies. The Pelvic Pain Urgency/Frequency (PUF) Patient Survey, created by C. Lowell Parsons, is a short questionnaire that will help doctors identify if pelvic pain could be coming from the bladder. The KCl test, also known as the potassium sensitivity test, uses a mild potassium solution to test the integrity of the bladder wall. 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. The previous gold standard test for IC/BPS was the use of hydrodistention with cystoscopy. Researchers, however, determined that this visual examination of the bladder wall after stretching the bladder was not specific for IC/BPS and that the test, itself, can contribute to the development of small glomerulations (that is, 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. 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.

Oral Medications
As recently as a decade ago, treatments available were limited to the use of astringent instillations, such as chlorpactin (oxychlorosene) or silver nitrate, designed to kill "infection" and/or strip off the bladder lining. In 2005, our understanding of IC/BPS has improved dramatically and these therapies are now no longer done. Rather, IC/BPS therapy is typically multi-modal, including the use of a bladder coating, an antihistamine to help control mast cell activity and a low dose antidepressant to fight neurogenic inflammation.

Pentosan polysulfate
Oral pentosan polysulfate is believed to provide a protective coating in the bladder, but studies show it is not statistically significant compared to placebo. However, some studies have found that a minority of patients do respond to pentosan polysulfate.

Amitriptyline
Amitriptyline can reduce symptoms in patients with IC/BPS. Patient overall satisfaction with the therapeutic result of amitriptyline was excellent or good in 46%. A May 2010 study concluded in part that amitriptyline may be beneficial in doses greater than 50 mg.

Duloxetine
The antidepressant duloxetine was found to be ineffective as a treatment. There is a U.S. Patent 6150396 for the use of duloxetine for treatment of interstitial cystitis although one study found positive outcomes in only a small proportion of cases. There has been further work to suggest that neuropathic pain localized in the pelvic region may respond to neurotransmitter reuptake inhibitors.

DMSO
DMSO, a wood pulp extract, is the only approved bladder instillation for IC/BPS yet it is much less frequently used in urology clinics. 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 of creating irreversible muscle contraction. However, a lesser solution of 25% was found to be reversible. Long term use is questionable, at best, particularly given the fact that the method of action of DMSO is not fully understood.

Rescue instillations
More recently, the use of a "rescue instillation" composed of pentosan polysulfate or heparin, sodium hyaluronate, lidocaine and sodium bicarbonate, has generated considerable excitement in the IC/BPS community because it is the first therapeutic intervention that can be used to reduce a flare of symptoms. Published studies report a 90% effectiveness in reducing symptoms.

Sometimes these rescue instillations are given on a regular basis for treatment. It is important to note that this is off-label use for both pentosan polysulfate and heparin, as neither medicine has been approved to be used this way.

Bladder coatings
Other bladder coating therapies include Cystistat (sodium hyaluronate) and Uracyst (chondroitin). They are believed to replace the deficient GAG layer on the bladder wall. Like most other intravesical bladder treatments, this treatment may require the patient to lie for 20 – 40 minutes, turning over every ten minutes, to allow the chemical to 'soak in' and give a good coating, before it is passed out with the urine.

Cystistat is not currently available in the United States or Canada, though testing has recently started in Canada. Testing has also begun for Uracyst in both Canada and the United States.

Diet
In 2007, a study done at Long Island University reported that over 90 percent of interstitial cystitis patients experience an increase in symptoms when they consume certain foods and beverages, especially coffee, tea, soda, alcoholic beverages, citrus fruits and juices, artificial sweeteners and hot pepper.

The American Urological Association states that most (but not all) people with IC find that certain foods make their symptoms worse.

The challenge with diet triggers is that they vary from person to person: the best way for a person to discover his or her own triggers is to use an elimination diet. The foundation of therapy is a modification of diet to help patients avoid those foods which can further irritate the damaged bladder wall.

Pain that worsened with a certain food or drink and/or worsened with bladder filling and/or improved with urination was reported by 97% of patients, in one study.

Anecdotal evidence has linked gluten intolerance to UCPPS symptoms. Studies are lacking in this area.

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:

"In animal models, pelvic inflammation is subject to crosstalk, so an inflammatory stimulus in one pelvic organ evokes a response in an independent organ. Recent data show that the colon can modulate bladder-associated pelvic pain in mice. As pelvic organs are innervated through shared circuitry, perceived pelvic pain might occur when spatial summation of individual pelvic inputs exceeds a threshold. Through this mechanism, a noxious dietary stimulus, which otherwise does not exceed the pain threshold in a normal individual, may substantially exacerbate pain in a patient with bladder symptoms. Repeated painful stimuli over time further contribute to symptoms by a process of temporal summation, resulting in enhanced responsiveness through central sensitization. Thus, pelvic organ crosstalk might modulate symptoms of pelvic pain by spatial and temporal summation."

A study done at University of South Florida found that IC/BPS patients do not have to be overly restrictive of their diets. This study recommended that patients avoid citrus fruits, tomatoes, coffee, tea, carbonated and alcoholic beverages, spicy foods, artificial sweeteners, and vitamin C. It also found that many patients had reduced sensitivity to trigger foods if they consumed calcium glycerophosphate and/or sodium bicarbonate.

Bladder distension
Bladder distension (a procedure which stretches the bladder capacity, done under general anaesthesia) has shown some success in reducing urinary frequency and giving pain relief to patients. However, many experts still cannot understand precisely how this can cause pain relief. Recent studies showing that pressure on pelvic trigger points can relieve symptoms may be connected. Unfortunately, the relief achieved by bladder distensions is only temporary (weeks or months) and consequently, it is not really viable as a long-term treatment for IC/BPS.

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 when all other treatment modalities have failed and pain is severe. Some patients who opt for surgical intervention continue to experience pain after surgery. Surgical interventions for IC/BPS include transurethral fulguration and resection of ulcers, using electricity/laser; bladder denervation, where some of the nerves to the bladder are cut (Modified Ingelman-Sundberg Procedure); bladder augmentation; bladder removal (cystectomy); electrical nerve stimulation, similar to TENS, where an electrical unit is implanted in the body and provides continuous or intermittent electrical pulses to the affected areas (Interstim); spinal cord stimulation (SCS), where an electrical unit is implanted that provides electrical stimulation to the spinal cord, interfering with pain reception to the brain (ANS/Advanced Neuromodulation Systems spinal Cord Stimulator); and the implantation of the intrathecal pain pump, where very small amounts of medication, like morphine sulfate, dilaudid, or baclophen are released into the cerebrospinal fluid via a catheter stemming from the small electrical pump, requiring only about 1/100 to 1/300 the amount of medication needed orally for the same therapeutic benefit, but with significantly fewer side effects.

Pain control
Pain control is usually necessary in the IC/BPS treatment plan. The pain of IC/BPS has been rated equivalent to cancer pain and may lead to central sensitization if untreated.

Medication
The use of a variety of traditional pain medications, including opiates and synthetic opioids like tramadol, is often necessary to treat the varying degrees of pain. Even children with IC/BPS should be appropriately addressed regarding pelvic pain, and receive necessary treatment to manage it.

Pelvic floor treatments
Work by Wise and Anderson (see details) has shown that urologic pelvic pain syndromes, such as IC/BPS and CP/CPPS, may have no initial trigger other than anxiety, often with an element of Obsessive Compulsive Disorder or other anxiety-spectrum problem. 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 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.

Most major IC/BPS clinics now evaluate the pelvic floor and/or refer patients directly to a physical therapist for a prompt treatment of pelvic floor muscle tension or weakness. Chronic pelvic floor tension can cause pain in the bladder and/or pelvis, which is often described by women as a burning sensation, particularly in the vagina. Men with pelvic floor tension experience referred pain, particularly at the tip of their penis. In 9 out 10 IC/BPS patients struggling with painful sexual relations, muscle tension is the primary cause of that pain and discomfort. Tender trigger points —small, tight, hyperirritable bundles of muscle— may also be found in the pelvic floor.

Pelvic floor dysfunction is a fairly new area of specialty for physical therapists world wide. 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 incontinence. Thus, traditional exercises such as Kegels, 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. While weekly therapy is certainly valuable, most providers also suggest an aggressive self-care regimen at home to help combat muscle tension, such as daily muscle relaxation audiotapes, stress reduction and anxiety management on a daily basis. Anxiety is often found in patients with painful conditions and can subconsciously trigger muscle tension.

Thiele massage
Transvaginal manual therapy of the pelvic floor musculature (Thiele massage) has shown promise in relieving the pain associated with Interstitial cystitis in at least one open, clinical pilot study.

Neuromodulation
Neuromodulation can be successful in treating IC/BPS symptoms, including pain. Electronic pain-killing options include TENS. PTNS stimulators have also been used, with varying degrees of success. Percutaneous sacral nerve root stimulation (PNS) was able to produce statistically significant improvements in several parameters, including pain.

Acupuncture
A 2002 review study reported that acupuncture alleviates pain associated with IC/BPS as part of multimodal treatment. While a 1987 study showed that 11 of 14 (78%) patients had a >50% reduction in pain, another study (published in 1993) found no beneficial effect. A 2008 review found that although there are hardly any controlled studies on alternative medicine and IC/BPS, "rather good results have been obtained" when acupuncture is combined with other treatments.

Biofeedback
Biofeedback, a relaxation technique aimed at helping people control functions of the autonomous 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.

Quality of Life
A survey conducted by the Urban Institute of Washington showed that among interstitial cystitis sufferers:
 * 40% were unable to work
 * 27% were unable to have sex due to pain
 * 27% had marriage breakdown
 * 55% contemplated suicide
 * 12% had attempted suicide

Further QoL evidence:
 * Prior studies have suggested that urologic chronic pelvic pain syndromes (UCPPS) can have severe adverse impact on quality of life (Temml, et al., 2003; Nickel et al., 2005). Population-based studies (e.g. Michael, et al., 2000) using the SF-36 have found significant decrease in QoL dimensions, including role/physical, bodily pain, vitality and social function, results that were supported by Rothrock's (et al., 2002) cross-sectional study of IC patients showing decreased physical functioning, decreased ability to function in one's normal role, decreased vitality, and depression.

Other research has shown that the impact of IC/BPS on Quality of Life is as severe as that of endstage renal disease and rheumatoid arthritis.

Countries are increasingly recognizing how severely IC/PBS can affect patients' lives, by officially recognizing that it can completely impair functioning. Countries in which Interstitial Cystitis/Painful Bladder Syndrome IC/PBS is now recognized with an official disability code:
 * United States of America

History

 * 1808 Dr. Phillip Syng Physic describes an inflammatory condition of the bladder producing the same lower urinary tract symptoms as a bladder stone [referenced in archival material, Philadelphia College of Physicians][53]
 * 1836 Dr. Phillip Syng Physic expands this concept to include a chronic frequency, urgency and pain syndrome occurring in the absence of demonstrable etiology[53]
 * 1836 Philadelphia surgeon Joseph Parrish (Dr. Phillip Syng Physic's mentee) publishes earliest record of interstitial cystitis, in 1836 textbook by Physic's mentee [53]
 * 2002 In the U.S.A., the Social Security Act is amended to include interstitial cystitis as a disability: 'This Ruling explains that IC (a complex, chronic bladder disorder), when accompanied by appropriate symptoms, signs, and laboratory findings, is a medically determinable impairment that can be the basis for a finding of "disability"'.[54]
 * 2004 American research study on interstitial cystitis history — earliest known descriptions of bladder inflammation and interstitial cystitis [53]
 * 2009 Release of Japanese guideline for diagnosis and treatment of interstitial cystitis
 * 2011 The American Urological Association releases the first-ever American clinical guidelines for diagnosing and treating interstitial cystitis/bladder pain syndrome (IC/BPS)[55]

Links to 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, vulvodynia, chemical sensitivities and anxiety disorder. In addition, men with IC/BPS 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 share the same etiology and pathology.