Definition of Interstitial Cystitis
Interstitial cystitis, or bladder pain syndrome (also IC/BPS), is a chronic condition and diagnosis of exclusion of unknown cause characterized by bladder pain. It may be associated with urinary urgency, urinary frequency, waking at night to urinate (nocturia), and sterile urine cultures. 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. 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.
Cause of Interstitial Cystitis
The cause of IC/BPS is currently unknown, 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. 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 develop IC. Current evidence from clinical and laboratory studies confirms that mast cells play a central role in IC/PBS possible due to their ability to release histamine and cause pain, swelling, scarring, and interfere with healing. 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.
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 orsodas, 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. 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.
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.
Numerous studies have noted the link between IC, anxiety, stress, hyperresponsiveness, and panic. Another proposed etiology for interstitial cystitis is that the body’s immune system attacks the bladder. Biopsies on the bladder walls of people with IC usually contain mast cells. Mast cell 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. 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.
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.
Signs and Symptoms of Interstitial Cystitis
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 pain, frequency, painful sexual intercourse, and nocturia.
In general, symptoms are:
- Painful urinationUrinary frequency (as often as every 10 minutes), urgency, and pressure in the bladder and/or pelvis.Urinary frequency (as often as every 10 minutes), urgency, and pressure in the bladder and/or pelvis.
- 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 patients are found to have Hunner’s ulcers. 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.
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, vulvodynia, chemical sensitivities, allergies, Sjogren’s syndrome, Systemic lupus erythematosus, and anxiety disorder. 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.
Risk Factors for Interstitial Cystitis
Interstitial cystitis is more common in these persons:
- People at their 40s.
- People have a history of urinary tract infections
- Getting irritable bowel syndrome
- Getting pain disorders, such as fibromyalgia or chronic fatigue syndrome
Diagnosis of Interstitial Cystitis
A diagnosis of IC/BPS is one of exclusion, as well as a review of clinical symptoms. 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. 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 helpul. 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 (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.
Prevention from Interstitial Cystitis
There are no way to prevent interstitial cystitis because the cause is unknown. But these are recomended to prevent from repeated bladder infections:
- Drink plenty of liquids, especially water.
- Don’t delay using the toilet when you feel the urge to urinate,
- Wipe from front to back after a bowel movement to prevent bacteria in the anal region.
- Take showers rather than tub baths
- Gently and daily wash the skin around the vagina and anus
- Empty your bladder as soon as possible after intercourse
- Avoid using deodorant sprays or feminine products in the genital area
Treatment of Interstitial Cystitis
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. The authors note their goal of providing insights for both healthcare providers and patients about managing this chronic condition. The Guideline outlines principles of clinical care—with the ultimate goal of improving the quality of life for IC patients.
The AUA Treatment Guidelines include a treatment protocol ranging from conservative treatments to more invasive interventions with lower numbers representing less invasive methods:
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.
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, understanding of IC/BPS improved dramatically and these therapies are now no longer used. 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. Oral pentosan polysulfate is believed to provide a protective coating in the bladder, but studies have encountered mixed results when attempting to determine if the effect is statistically significant compared to placebo.
Amitriptyline has been shown to be effective in reducing symptoms in many patients with IC/BPS with a median dose of 75 milligrams daily. In one study, the antidepressant duloxetine was found to be ineffective as a treatment , although a patent exists for use of duloxetine in the context of IC, and is known to relieve neuropathic pain.
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 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 and analgesic effects.
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.
Other bladder coating therapies include Cystistat (sodium hyaluronate) and Uracyst (chondroitin). These treatments 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. Uracyst is available in Canada.
Interstitial cystitis patients often experience an increase in symptoms when they consume certain foods and beverages, especially caffeine-containing beverages such as coffee, tea, and soda. Dietary triggers may also include alcoholic beverages, citrus fruitsand juices, artificial sweeteners and hot peppers. 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. Patients may be able to reduce sensitivity to trigger foods if they consume calcium glycerophosphate and/or sodium bicarbonate. The foundation of therapy is a modification of diet to help patients avoid those foods which can further irritate the damaged bladder wall.
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.
Bladder distension (a procedure which stretches the bladder capacity while 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 procedure causes pain relief. 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.
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 theintrathecal pain pump, where very small amounts of medication, like morphine sulfate, dilaudid, or baclofen 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.
Pelvic Floor Treatments
Research by Wise and Anderson 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.
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.
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.
Pain Control Therapies
Neuromodulation can be successful in treating IC/BPS symptoms, including pain. One electronic pain-killing option is 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.
A 2002 review study reported that acupuncture alleviates pain associated with IC/BPS as part of multimodal treatment. While a small 1987 study showed that 11 of 14 (78%) patients had a >50% reduction in pain, a 1993 study found no beneficial effect. 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. 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.