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Bladder Pain Syndrome and Interstitial Cystitis: Definition and Etiology

• Interstitial cystitis: definition, causes, symptoms and diagnosis
• Interstitial cystitis: medical treatment and surgical therapy

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

Bladder pain syndrome (BPS)/Interstitial cystitis (IC) is a disease of unknown etiology presenting with frequency, bladder pain, and decreased bladder capacity (Loch and Stein, 2004).

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 of interstitial cystitis is reserved for 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 six 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 visible lesions in cystoscopy. Since the significance of the cystoscopic findings (see below) is doubted, the classification has lost its importance.

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. Inflammatory mast cell activation leads to increased permeability of the urothelium, fibrosis, and reduction of bladder capacity.

Increased Permeability of the Urothelium:

An impaired glycosaminoglycan layer leads to a leaky urothelium, and toxic substances, allergens, or bacteria may invade the deeper bladder wall layer and cause an inflammatory process. It is unclear whether the increased permeability of urothelium in patients with interstitial cystitis is the primary step in the pathophysiology or a consequence of an inflammatory cascade.

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. The central role of mast cells in the inflammatory cascade of interstitial cystitis is undisputed in IC research. Overall, the infectious theory is seen at best as a trigger for 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 neurogenic inflammation is indistinguishable from a bacterial or allergic inflammation cascade. The threshold at which the bladder filling is perceived as painful is significantly reduced in patients with interstitial cystitis. Recurring pain stimuli could trigger the neurogenic inflammatory cascade, and maladaptive mechanisms may lead to 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, but the laboratory findings' specificity is controversial. Secondary autoimmune phenomena 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 Causes

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 classic interstitial cystitis with histological signs of inflammation and ulceration visible in cystoscopy or into non-ulcer interstitial cystitis without histological signs of inflammation and visible lesions has not proven 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 of pathology is to exclude other possible diseases like carcinoma in situ.

Macroscopic findings:

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

Microscopic findings:

Mast cell infiltration of the bladder wall, infiltrates of lymphocytes, ulcerative defects of the urothelium, and 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 or discomfort is perceived in the bladder region.
• At least one other urinary symptom: frequency, nocturia, or urgency
• Duration of symptoms for at least six 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), IC Problem Index (ICPI), and University of Wisconsin IC Scale (UW-IC Scale).

Diagnosis of Bladder Pain Syndrome and Interstitial Cystitis

Prerequisites for diagnosing "bladder pain syndrome" or "interstitial cystitis" are symptoms mentioned above without any explanatory etiology. Crucial for the diagnosis is excluding the long list of differential diagnoses, see differential diagnosis below.

Micturition protocol:

A micturition protocol helps assess the 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:

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

• Glomerulations: punctate mucosal bleeding after bladder distention, present in 90% of IC patients.
• Hunner ulcers: bleeding ulcerative lesions of the urothelium after bladder distention, present in one out of ten IC patients.

Optional Tests

Potassium Chloride Test:

Intravesical KCl (0.4 M) produces pain in many 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 specificity 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.

Differential diagnosis of the Bladder Pain Syndrome

• 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: estrogen deficiency, endometriosis, infections (vaginitis, salpingitis), cancer of the cervix, ovary or endometrium.
• Radiation therapy of pelvic organs
• Side effects of drugs like cyclophosphamide or ketamine

References

Keay, S. Cell signaling in interstitial cystitis/painful bladder syndrome.
Cell Signal, 2008, 20, 2174-2179.

Loch, A. & Stein, U. [Interstitial cystitis. Current aspects of diagnosis and therapy].
Urologe A, 2004, 43, 1135-1146.

Oberpenning u.a. 2000 OBERPENNING, F. ; OPHOVEN, A. van ; HERWIG, R. ; PIECHOTA, H. J.: [Diagnosis of interstitial cystitis].
In: Urologe A
39 (2000), Nr. 6, S. 530–4

Sievert u.a. 2000 SIEVERT, K. D. ; EDENFELD, K. D. ; OBERPENNING, F. ; PIECHOTA, H. J.: [Oral therapy of interstitial cystitis].
In: Urologe A
39 (2000), Nr. 6, S. 535–8

  Deutsche Version: Interstitielle Zystitis