Editors

MikaelLeppilahti

Bladder Pain Syndrome (Interstitial Cystitis)

Essentials

An international working group of urologists has proposed abandoning the term "interstitial cystitis" (IC) and replacing it with the term "bladder pain syndrome". Since IC has become rooted as the general name, the current recommendation for an abbreviation is BPS/IC (Bladder Pain Syndrome/Interstitial Cystitis).
Even though BPS/IC is a rare syndrome it is more prevalent than is generally thought.
The majority of patients remain undiagnosed and receive treatment for the symptom picture of recurrent urinary tract infections although culture specimens are clean.
Clinical diagnosis is based on symptoms (urinary frequency, urgency, nocturia, dyspareunia and lower abdominal pain which increases as the bladder fills).
There are no specific signs or diagnostic criteria. Foremost for the diagnosis is the use of hydrodistention during cystoscopy, after which the physician will look for the presence of petechial haemorrhages (glomerulations) and/or for the so-called Hunner's ulcers (circumvallated lesions, the histological finding of which will show an immunological inflammation).
In urodynamic studies, the activation of sensory nerves causes painful feelings of urinary urgency without simultaneous bladder contractions at bladder filling of less than 150 ml.
The need for patient education and support is great.
Amitriptyline should be tried as the first line drug.

Epidemiology

The prevalence in women is ten times higher than in men.
The worldwide prevalence estimates vary between 4.5-870/100 000 individuals.

Aetiology

Unclear and likely to have a multifactorial aetiology; the condition should be considered a clinical syndrome rather than a specific illness.
BPS/IC with Hunner's lesion is an essential distinct subtype whose characteristics are submucous chronic inflammation and immunological changes.
BPS/IC without Hunner's lesion is not associated with histological findings. There is underlying increased neuropeptide secretion of the peripheral nerves which causes increased sensitivity of afferent nerves and mast cell-mediated neurogenic inflammation.
In recent years, the changes of microbiome have been researched intensively, but for the time being evidence on its significance for inflammation mechanisms has not been confirmed.

Diagnosis

Based on clinical symptoms: urinary frequency, urgency, nocturia, dyspareunia and lower abdominal pain which increases as the bladder fills and is temporarily alleviated after urination.
O'Leary-Sant Interstitial Cystitis Symptom and Problem Questionnaires (see tables T1 and T2) have been validated in clinical practice. It is most suitable for the assessment of treatment response, but it is not a specific diagnostic tool.
Diseases to be excluded: bacterial infection, tuberculosis gynaecological diseases (endometriosis, malignancy, vaginitis, prolapse, pudendal nerve entrapment), painful condition of the pelvic muscles, back problems, intestinal diseases, prostatic diseases (prostatitis, prostate cancer, urinary retention), urethral diverticulum, lower urinary tract stone, radiation- or drug-induced cystitis, genital herpes, carcinoma in situ of the urinary bladder, or neurogenic urinary disorders (hyperreflexia/instability).
Urine culture and cytology.
Urodynamic studies may be suggestive of BPS/IC, i.e. the first urge to void may appear when the bladder is filled with less than 100 ml (and almost always at 150 ml), with a maximum bladder capacity of less than 400 ml.
BPS/IC is also characterised by petechial mucosal haemorrhages (glomerulations) brought on by hydrodistension of the bladder during general anaesthesia. Dilatation-induced tearing of mucosa and oozing of blood without glomerulations should, however, not be interpreted as petechial hemorrhages.
Diagnostic dilatation will temporarily alleviate the symptoms, confirming that the problem originates from the bladder. If dilatation does not alleviate the symptoms even for a few days, the symptoms most likely have their origin outside the bladder.
Hunner's lesion is a pain spot in the bladder, and its cauterization or electroresection will bring long-term relief.

Interstitial Cystitis Symptom Index

Read each question carefully and circle the number of the answer that best describes your own experiences.
1. During the past month, how often have you felt a strong need to urinate with little or no warning?	0. Not at all
	1. Less than 1 time in 5
	2. Less than half the time
	3. About half the time
	4. More than half the time
	5. Almost always
2. During the past month, have you had to urinate less than two hours after you finished urinating?	0. Not at all
	1. Less than 1 time in 5
	2. Less than half the time
	3. About half the time
	4. More than half the time
	5. Almost always
3. During the past month, how often did you most typically get up at night to urinate?	0. Not once
	1. Once per night
	2. Twice per night
	3. Three times per night
	4. Four times per night
	5. Five times or more per night
4. During the past month, have you experienced pain or burning in your bladder?	0. Not at all
	1. A few times
	2. Fairly often
	3. Usually
	4. Almost always

Total score of 0-3 points is a normal result, 4-6 mild symptoms, 7-11 moderate symptoms and 12 or over severe symptoms.

Interstitial Cystitis Problem Index

During the past month, how much has each of the following symptoms been a problem for you?
1. Frequent urination during the day?	0. No problem
	1. Very small problem
	2. Small problem
	3. Medium problem
	4. Big problem
2. Getting up at night to urinate?	0. No problem
	1. Very small problem
	2. Small problem
	3. Medium problem
	4. Big problem
3. Need to urinate with little warning?	0. No problem
	1. Very small problem
	2. Small problem
	3. Medium problem
	4. Big problem
4. Burning, pain, discomfort or pressure in your bladder?	0. No problem
	1. Very small problem
	2. Small problem
	3. Medium problem
	4. Big problem

Total score of 0-3 points is a normal result, 4-6 mild problem, 7-11 moderate problem and 12 or over severe problem.

Treatment methods

There is no known curative treatment and all therapies are empirical. The response to different treatments varies greatly, supporting the assumption of a multifactorial aetiology.
The symptoms are mild in the majority of patients, and in long-term follow-up the symptoms will abate without particular treatment in almost half of patients.
Patients will benefit from a long term doctor-patient relationship as well as from personal guidance and support.

Self-care

The symptoms may be aggravated by external irritants, e.g. many foodstuffs (strong spices, coffee, citrus fruits, red wine, carbonated drinks, chocolate, tomatoes, bananas etc.) and exposure to cold. However, unnecessary dietary restrictions must be avoided.

Drug treatment

Analgesics
- Conventional anti-inflammatory drugs do not work well because the pain mechanism in BPS/IC is not based on a prostaglandin-mediated inflammatory mechanism.
- Central analgesics work directly on the central nervous system and are more effective in most patients.
Amitriptyline
- Blocks acetylcholine receptors, inhibits reuptake of serotonin and noradrenaline, blocks histamine H₁ receptors and has an anxiolytic effect. Used the same way as in chronic pain syndromes.
- First line drug treatment and will, in most patients, suffice as the sole long-term agent. The dose is increased in increments of 10 mg/week up to 50-75 mg/24 hours. If indicated, other treatment forms, e.g. bladder instillations, may be added. About half of the patients benefit from the treatment within 2-year follow-up.
Ciclosporin
- Use requires expertise and continuous monitoring.
- 70% of patients, some with severe BPS/IC, improved significantly with regular medication. The treatment response is usually lost when the medication is withdrawn.

Intravesicular treatments (bladder instillations) Intravesical Treatments for Painful Bladder Syndrome/ Interstitial Cystitis

DMSO (dimethyl sulfoxide)
- Neutralises urinary toxins and intracellular oxygen radicals, suppresses interleukin-8, acts on the mast cells and pain-sensing C-fibre nerve endings, breaks down antibodies, reduces pain and relaxes the smooth muscle.
- Despite its unspecific nature, DMSO is the cornerstone of treatment in patients with severe symptoms. The initial treatment consists of 4-6 instillations of DMSO, which are carried out at weekly intervals. According to response, the maintenance treatment may then continue every 4-6 weeks. DMSO is safe even when used for several years.
Therapies targeted at the glucosaminoglycan (GAG) layer
- Therapies have been developed with the assumption that the GAG layer of the mucosa would be damaged. However, the real mechanism of action is likely based more on the anti-inflammatory properties of these preparations.
- The initial treatment usually consists of 4-6 instillations, which are carried out at weekly intervals, followed by treatment once a month, provided that a good response is achieved. It may be tried in cases where DMSO is not suitable for some reason.
BCG instillations
- Used for the treatment of superficial bladder carcinoma.
- Has a strong effect on cell-mediated immune mechanisms.
- Positive results in the treatment of BPS/IC have been reported in individual patients, but instillations in most cases result in severe bladder irritation that may persist for several months. Not recommended due to the adverse effects.

Hydrodistension

The oldest, and perhaps still the most used, symptomatic treatment in BPS/IC.
However, prolonged and repeated hydrodistensions will damage the bladder causing scarring, and such distensions will further reduce the bladder capacity.
A diagnostic distension (80 cm H₂O) 1-3 times for one minute's time will improve the condition of most patients, at least for a short period. Should there be no improvement in the pelvic pain, consideration should again be given to differential diagnosis.

Sacral neuromodulation

An increasingly used treatment method if other treatment has not provided sufficient relief
Significant relief from pain, urinary frequency, nighttime urination and urinary urgency has been found.

Surgical treatment

Severely symptomatic BPS/IC may considerably impair the patient's quality of life, and it may even increase the risk of suicide 4-fold. Surgery, which has yielded partially good results, may be considered in the most difficult cases.
Urinary diversion alone may alleviate symptoms in some cases as no more urine will collect in the bladder. However, it often becomes necessary to remove the bladder at a later stage, and the removal of the bladder is therefore usually recommended at the time of the urostomy surgery.
Partial cystectomy, followed by a graft constructed from a bowel segment, has also been used. However, as the fundus of the bladder will be saved, the risk of pain and urinary urgency will remain after surgery.
Total cystectomy is likely to offer the most reliable symptom control. Depending on the patient's age and general health, either a urostomy or an orthotopic neobladder reconstruction may be chosen. In women, the neobladder (constructed from the patient's own intestines) usually functions well, provided that the patient had no problems with continence before the surgery.

References

Leppilahti M, Sairanen J, Tammela TL et al. Prevalence of clinically confirmed interstitial cystitis in women: a population based study in Finland. J Urol 2005;174(2):581-3. [PubMed]
Sairanen J, Tammela TL, Leppilahti M, et al. Cyclosporine A and pentosan polysulfate sodium for the treatment of interstitial cystitis: a randomized comparative study. J Urol 2005;174(6):2235-8. [PubMed]
Wang J, Chen Y, Chen J, et al. Sacral Neuromodulation for Refractory Bladder Pain Syndrome/Interstitial Cystitis: a Global Systematic Review and Meta-analysis. Sci Rep 2017;7(1):11031. [PubMed]
Colemeadow J, Sahai A, Malde S. Clinical Management of Bladder Pain Syndrome/Interstitial Cystitis: A Review on Current Recommendations and Emerging Treatment Options. Res Rep Urol 2020;12():331-343. [PubMed]
Akiyama Y. Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome with and without Hunner Lesion: A Review and Future Perspectives. Diagnostics (Basel) 2021;11(12):2238. [PubMed]
Walton I, Nickel JC. The Urinary Microbiome in Interstitial Cystitis/Bladder Pain Syndrome? A Critical Look at the Evidence. J Urol 2021;206(5):1087-1090. [PubMed]

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