Bladder Pain Syndrome and Interstitial Cystitis

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Definitions of Interstitial Cystitis (IC) and Painful Bladder Syndrome (BPS)

Bladder pain syndrome (BPS)/Interstitial cystitis (IC) is disease of unknown etiology which presents with frequency, bladder pain and decreased bladder capacity (Loch and Stein, 2004). Several definitions of the disease have been formulated in the past years, the most important ones are cited:

Definition of the NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases)

Interstitial cystitis is pain associated with the bladder or urinary urgency, and glomerulations or Hunner ulcers on cystoscopy under anesthesia, in patients with 9 months or more of symptoms (Wein et al, 1990). The following conditions exclude the diagnosis of interstitial cystitis:

• Bladder capacity >350 ml
• Absense of intense urge to void during rapid filling of the bladder >150 ml
• Autonomous detrusor contractions
• Absense of nocturia or <8 micturitions/day
• Active genital herpes
• Chemical cystitis, radiation cystitis or the bladder tuberculosis
• Bladder tumors

Relative exclusion criteria for the diagnosis of interstitial cystitis are complaints of less than 9 months, response to anticholinergic drugs, antibiotics or anticonvulsants, age younger of 18 years, vaginitis, bladder calculi or ureteral calculi.

Definition of the International Continence Society (ICS)

Bladder pain syndrome is the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven urinary tract infection or other obvious pathology. The diagnosis interstitial cystitis is reserved to patients with typical cystoscopic and histological features (Abrams et al, 2002).

Definition of the Society for Urodynamics and Female Urology

Bladder pain syndrome or Interstitial cystitis is an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than 6 weeks’ duration, in the absence of infection or other identifiable causes (Hanno and Dmochowski, 2009).

Classification of interstitial cystitis:

Interstitial cystitis can be classified into classic interstitial cystitis with histological signs of inflammation and ulceration visible in cystoscopy or non-ulcer interstitial cystitis without histological signs of inflammation and without visible lesions in cystoscopy.

Epidemiology of the Bladder Pain Syndrome

• Preval‎ence is 10–500/100 000 women, depending on the inclusion criteria. Modern studies show higher preval‎ence rates.
• Mean age at diagnosis is 40–50 years, female to male ratio = 9:1.

Causes of Bladder Pain Syndrome and Interstitial Cystitis

The etiology of interstitial cystitis is highly controversial and most likely multifactorial. Suspected causes are discussed in the following sections: mast cell activation, increased permeability of the urothelium, infection with unknown organisms and neurogenic inflammation.

Increased Permeability of the Urothelium:

An impaired glycosaminoglycan layer leads to a leaky urothelium and toxic substances, allergens or bacteria may invade deeper bladder wall layer and cause an inflammatory process. Whether the increased permeability of urothelium in patients with interstitial cystitis is the primary step in the pathophysiology or can be seen as a consequence of an inflammatory cascade is unclear. An impaired glycosaminoglycan layer can be detected using the potassium test (see below), which is positive in a subset of patients with bladder pain syndrome. The specifity of the test is low, because the potassium test is also positive in patients with bacterial cystitis or radiation cystitis. On the other hand, there are successful treatment options which rather damage the glycosaminoglycan layer (e.g. bladder distention). Increased urothelial permeability as a primary step of IC pathophysiology remains debatable.

Infection of the Urinary Bladder Wall:

Many attempts to prove an infectious etiology for interstitial cystitis have failed. Antibiotic treatment did not prove to be effective. It is still possible that harmless organisms trigger an autoimmune reaction against components of the bladder wall. This hypothesis is supported by increased mast cells and increased concentrations of their mediators in the urothelium and bladder wall. Undisputed in the IC research anyhow is the central role of mast cells in the inflammatory cascade of interstitial cystitis. Overall, the infectious theory is seen at best as a trigger for the interstitial cystitis.

Antiproliferative Activity of the Urine:

Studies have found an antiproliferative activity in the urine of patients with interstitial cystitis. The putative factor is called antiproliferative factor (APF), which is most probable produced in the bladder and belongs the frizzled protein family. Any injury of the bladder (infection, trauma or overdistension) may lead in susceptible patients (with APF) to bladder pain syndrome or interstitial cystitis. Further studies are needed to assess the clinical significance of APF (Keay, 2008).

Neurogenic inflammation:

Increased stimulation of pain fibers may cause a neurogenic inflammation. Increased concentrations of mediators of neurogenic inflammation, such as substance P, neurokinin A and calcitonin gene-related protein could be detected in interstitial cystitis. The inflammatory cascade of a neurogenic inflammation is indistinguishable from a bacterial or allergic inflammation cascade. The threshold at which the bladder filling is perceived painful is significantly reduced in patients with interstitial cystitis. Recurring pain stimuli could trigger the neurogenic inflammatory cascade and maladaptive mechanisms may lead to the chronic pain syndrome.

Autoimmunity and Interstitial Cystitis:

The relationship between interstitial cystitis and autoimmunity is contradictory. It was possible to detect autoantibodies against the urinary bladder, the specificity of the laboratory finding is controversial. Secondary autoimmune phenomenons in response to inflammation are also possible. Although the non-specific inhibition of the inflammatory cascade is part of the effective therapy, the exact role of autoimmunity remains unclear.

Psychosomatic Etiology

Psychological stress and derived symptoms are interpreted as a response to the disease (voiding almost hourly and suffering from chronic pain).

Pathology of Interstitial Cystitis

The historical classification of interstitial cystitis into a classic interstitial cystitis with histological signs of inflammation and ulceration visible in cystoscopy or into a non-ulcer interstitial cystitis without histological signs of inflammation and without visible lesions has not proven to be useful. The histological signs (if any are visible) are non-specific and cannot be correlated to the clinical situation. Furthermore, even electron microscopy fails to identify any pathological correlate for interstitial cystitis. The role for pathology is to exclude other possible diseases like carcinoma in situ.

Macroscopic findings:

Ulcerative lesions in the bladder (Hunner's ulcers) and glomerulations after bladder distention (punctate mucosal bleeding) were described to be associated with interstitial cystitis, but they be also present after e.g. radiation therapy. The sensitivity and specificity of the cystoscopic findings are controversial, they are present in only a small proportion of patients with bladder pain syndrome or interstitial cystitis. In the course of the disease, increasing fibrosis of the bladder wall leads to a diminished bladder capacity.

Microscopic findings:

Mast cell infiltration of the bladder wall, infiltrates of lymphocytes, ulcerative defects of the urothelium, small subepithelial hemorrhages. The histological signs (if any are visible) are non-specific and cannot be correlated to the clinical situation.

Signs and Symptoms of Bladder Pain Syndrome and Interstitial Cystitis

Basic symptoms:

• Pain, pressure or discomfort perceived to be related to the bladder
• At least one other urinary symptom: frequency, nocturia or urgency
• Duration of symptoms for at least 6 weeks without any explanatory etiology

Symptom scores:

Due to the varying intensity, several symptom scores were created to monitor the therapeutic effect: IC symptom index (ICSI) and IC Problem Index (ICPI), University of Wisconsin IC Scale (UW-IC Scale).

Diagnosis of Bladder Pain Syndrome and Interstitial Cystitis

Prerequisite for diagnosis "bladder pain syndrome" or "interstitial cystitis" are above mentioned basic symptoms without any explanatory etiology. Crucial for the diagnosis is the exclusion of the long list of differential diagnosis, see differential diagnosis .

Micturition protocol:

A micturition protocol is useful to assess frequency and voided volumes. Voided volumes of less than 250 ml, micturition at least every two hours and always nocturia are typical for interstitial cystitis.

Urine Analysis:

• Urine sediment and urine culture to exclude urinary tract infection
• Urine cytology: to exclude bladder cancer (especially carcinoma in situ).

Ultrasound imaging:

Ultrasound imaging is done to exclude kidney and bladder diseases.

Cystoscopy:

In patients with bladder pain syndrome, cystoscopy should be performed under general anesthesia. The bladder is distended under vision with a pressure of 80–100 cm H₂O for 2 min, a measurement of the bladder capacity is done. After re-filling the bladder is inspected for glomerulations, Hunner ulcers and for differential diagnosis. The sensitivity and specificity of the cystoscopic findings are controversial (see above). A quadrant biopsy of the bladder is done to exclude bladder cancer (carcinoma in situ).

Optional Tests

Potassium Chloride Test:

Intravesical KCl (0.4 M) produces pain in a subset of patients with bladder pain syndrome. The potassium chloride test claims to indicate abnormal epithelial permeability. Clinical studies failed to prove any benefit in the management of patients with bladder pain syndrome and interstitial cystitis, since the sensitivity and specifity is very low.

Urodynamics:

Urodynamic studies are useful in unclear cases with bladder pain syndrome, especially to exclude an overactive bladder. Cystometry usually reveals pain on bladder filling and a normal detrusor function.

Potential urinary markers:

Since interstitial cystitis/bladder pain syndrome is a diagnosis based on a symptom-complex, urinary markers are "only" helpful in the context of clinical research. Promising markers are antiproliferative factor (AFP), measurement of nitric oxide in the air instilled and incubated in the bladder, and Uroplakin III-delta 4.

Differential diagnosis of the Bladder Pain Syndrome

• Bacterial infections: acute cystitis, schistosomiasis, urogenital tuberculosis
• Neurological diseases with bladder symptoms
• Diseases of the prostate: bacterial prostatitis, prostate cancer
• Bladder stones
• Bladder cancer, especially carcinoma in situ of the urinary bladder
• Gynecological diseases: endometriosis, infections (vaginitis, salpingitis), cancer of the cervix, ovary or endometrium.
• Radiation therapy of pelvic organs
• Side effects of drugs like cyclophosphamide