Interstitial cystitisN30.1

As early as 1808, Dr. Phillip Syng Physick was the first to describe interstitial cystitis (Tunn 2010). It was recorded in detail by Dr Alexander Skene in 1887 (Partin 2020) as "An inflammation that has distroyed the mucous membrane partly or wholly and extended to the muscular parietes". In 1915, Hunner described a particular form of bladder ulceration in IC, which was subsequently named after him as "Hunner's lesions". In 2008, the European Society for the Study of Interstitial Cystitis (ESSIC) proposed the additional name "Bladder Pain Syndrome" (BPS) (Bschleipfer 2018).

Interstitial cystitis (IC / BPS) has not yet been defined uniformly worldwide.

According to the S2K guideline, IC is a chronic inflammatory disease of the urinary bladder, which, in addition to the symptom complex of BPH (chronic lower abdominal pain without evidence of inflammation), may also show histological and / or cystoscopic changes (Bschleipfer 2018).

Associated autoimmune diseases exist in up to 40% of patients such as:

- rheumatoid arthritis

- Sjögren's syndrome

- scleroderma

- lupus erythematosus

- Hashimoto's thyroiditis

(Hegele 2015)

IC is divided into 2 subtypes:

• 1. Hunner type: Here, cystoscopic ulcerative changes, so-called "Hunner lesions" are detectable and additionally punctate mucosal bleeding of the urinary bladder (so-called "glomerulations" [Manski 2019]). Type 1 occurs rarely (in about 10% of cases. Kasper 2015, Bschleipfer 2018).
• 2nd non-Hunner type: In type 2, no Hunner lesions are detectable under or after bladder distension (Bschleipfer 2018). However, glomerulations are found in up to 90% of patients (Manski 2019).

IC occurs in all age groups, even in young children and adolescents. It occurs most frequently in middle-aged persons (frequency peak between 42 - 53 years) (Hegele 2015).

Women are affected up to 9 times more frequently than men. The prevalence in women is 52 - 500 / 100,000, in men between 8 - 41 / 100,000 (Bschleipfer 2018).

In the USA, the prevalence in women is between 3 % - 6 % and in men between 2 % - 4 %.

However, since usually only patients with severe symptoms seek medical care, the number of unreported cases is probably high (Kasper 2015).

In about 1/3 of patients, bacterial cystitis is present at the onset of IC (Kasper 2015). However, the exact cause of IC is not yet known (Kuhlmann 2015). One suspected the upregulation of sensory sensations in the brain. However, studies to date have not demonstrated abnormal pain sensitivity in IC sufferers (Kasper 2015).

The following factors are discussed etiologically:

1. urothelial dysfunction: Dysfunction results in increased permeability of the urinary bladder mucosa. In particular, penetration of potassium into the interstitium can cause typical symptoms of IC (Bschleipfer 2018).

2. inflammatory changes: high concentrations of immunoglobulin, B and T cells, inflammation-supporting cytokines and leukotrienes as well as other inflammatory markers are present. These changes occur in Hunner- type (Bschleipfer 2018).

3. neuronal overactivity: Here, neuropathic pain occurs due to dysfunction or damage of the nervous system. Hypersensitivity and spontaneous pain are triggered by harmless stimuli. (Bschleipfer 2018)

4. Impaired microcirculation: Increased expression of angiogenic growth factors and death of endothelial cells in the urinary bladder area are found. Due to dysregulated or increased angiogenesis, mucosal bleeding occurs. (Bschleipfer 2018)

5. exogenous substances: patients with IC complain of food intolerances in almost 90%, particularly affected are citrus fruits, horseradish, tomatoes, pepper, vinegar, glutamate, sugar substitutes, etc.... There is a correlation between the intake of certain foods and the appearance of the symptoms of IC in affected patients through pathological mechanisms. (Bschleipfer 2018)

6. histamine intolerance: It is possible that another food intolerance - histamine intolerance - plays a role. In a retrospective study, 65% of IC patients (n = 97) had elevated histamine levels in their stool. The exact pathomechanism has not yet been sufficiently clarified, especially since there is currently no test method for diagnosing histamine intolerance that is recognized by conventional medicine. (Bschleipfer 2018)

7. infections: In the current literature, the relationship between urinary bladder infection and IC is controversially discussed. However, it is striking that women with recurrent urinary tract infections show alterations that may explain the hypersensitive symptoms, such as:

• increased rate of cell apoptosis in the urothelium
• increased number of mast cells
• decreased number of E- Cadherin (essential protein that connects single cells together [Woichansky 2016]) (Bschleipfer 2018)

8. pelvic floor dysfunction: 50%-87% of patients with IC have pelvic floor hypertension, often with abnormal musculoskeletal findings (delayed or absent relaxation and decreased strength, endurance, and coordination)(Bschleipfer 2018)

9. visceral crosstalk between bowel and urinary bladder: the most common comorbidity in IC is irritable bowel syndrome. The so-called "leaky gut syndrome", in which damaged "tight junctions" are present in the intestinal epithelial layer, appears to be a trigger for food allergies or sensitivities, among other things (Bschleipfer 2018).

10. endometriosis: patients suffering from endometriosis sometimes have a parallel IC. In 2013, Tirlapur et al. were able to demonstrate in a retrospective study that both diagnoses existed simultaneously in 48% of patients. This should be taken into account when taking a medical history and, if necessary, appropriate therapy for endometriosis should be initiated (Bschleipfer 2018).

11. non-urinary bladder associated factors: Often found in patients with IC concomitant diseases such as:

• Autoimmune diseases
• general exhaustion up to chronic fatigue syndrome (CFS)
• functional somatic syndrome
• fibromyalgia etc.
• previous pelvic surgery such as hysterectomy.
• The severity of IC correlates with the presence of non-urinary bladder associated conditions (Bschleipfer 2018). The existing concomitant diseases are often referred to as so-called "functional somatic syndromes = FSS". Due to the comorbidity, IC is also often referred to as FSS (Kasper 2015).

Psychosomatic stress disorders

Criterion A: This includes somatic symptoms that lead to disruptions in daily life.

Criterion B: Psychological characteristics that relate to the

• Relate to the seriousness of the symptoms present (so-called cognitive dimension).
• persistent marked anxiety about existing symptoms and about health in general (so-called emotional dimension)
• Excessive expenditure of energy and time on health concerns (so-called behavioural dimension).

Criterion C: Persistent symptom burden of > 6 months. (Bschleipfer 2018)

13. microbiome: Microbiome research is currently making great progress. From it, new diagnostic and therapeutic approaches for the treatment of IC could possibly emerge. For example, compared to healthy women, DNA sequencing of urine shows a reduced bacterial diversity together with an excess of lactobacilli. PCR examinations of the stool also revealed differences compared to healthy individuals in the form of reduced concentrations of Eggerthella sinensis, Lactonifactor longoviformis, Odoribacter splanchnicus, Collinsella aerofaciens and Fae- calibacterium prausnitzii. Further findings are currently awaited (Bschleipfer 2018).

14. genetics: The role of genetic factors could not be clearly proven so far, but are possible (Bschleipfer 2018).

Normally, the urothelium is protected from harmful components of the urine by a glycosaminoglycan-containing layer. In the case of IC, this protective mechanism is disrupted. This allows toxic components of the urine to penetrate into deeper layers of the bladder wall.

Potassium plays a particularly important role in this process, causing depolarization of the nerve and muscle cells and thus triggering the clinical symptoms such as pain and urinary urgency.

In addition, the penetrated antiproliferation factors impede mast cell degranulation and urothelial regeneration (Risler 2008).

The typical triad of IC are:

• Pollakisuria
• Bladder pain
• decreased urinary bladder capacity

(Manski 2019)

The symptoms appear gradually in some of the patients. Others can give the exact date of first onset. In more than half of the latter group, symptomatology begins with dysuria(Kasper 2015).

The symptomatology persists over a long period of time and is characterized by recurrent episodes of varying intensity (Risler 2008).

In IC, there may be:

• Pain with p. m.
  • suprapubic so-called alguria (Herold 2021) is found in 80%.
  • in the area of the urethra in 35 %
  • non-urogenital areas (e.g. lower back, buttocks, thighs) in 30 %
  • vulva in 25

Pain worsens with bladder filling in up to 95% of patients and >50% of patients report an increase in pain intensity with ingestion of certain foods, menstruation, tight clothing, stress, after vaginal intercourse, etc. (Kasper 2015).

• strong urge to urinate (up to 60 x / 24 h) so-called pollakisuria
• sleep deprivation caused by frequent nocturia
• significantly reduced quality of life

The spectrum of symptom intensity can vary greatly....

(Kasper 2015)

Some patients also have:

• Joint pain
• Muscle pain
• large intestine or stomach problems
• allergic reactions
• Migraine

(Hegele 2015)

Since there is no specific test for the detection of IC, the diagnosis is based on the above-mentioned symptoms and the exclusion of infectious and structural diseases of the urinary bladder.

The diagnosis of IC can be excluded from the outset in the case of:

• absence of nocturia
• urinary bladder capacity of > 350 ml

(Kuhlmann 2015)

In a large number of patients, persistent or constantly recurring symptoms without bacteriuria - often only after years - lead to the diagnosis of IC.

(Kasper 2015)

The obligatory examinations in cases of suspected IC include:

• detailed anamnesis
• Micturition protocol over 2 - 7 days
• Pain questionnaire. The following questionnaires are available in English:
  • Pelvic Pain and Urgency / Frequency patient symptom scale" (PUF). This questionnaire deals with post-coital pain and pelvic pain and can localize them more closely. It can also be used to evaluate the success of treatment.
  • Bladder Pain /I C Symptom Score (BPIC- SS). This questionnaire is mainly used in clinical research.
  • O'Leary- Sant interstitial cystitis problem and symptom indices" (ICPI / ICSI). Xu et al. (2013) do not generally recommend the O' Leary- Sant questionnaire for the diagnosis of IC, because although the sensitivity is 98%, the specificity is very low at 8%. However, an OPSI threshold of ≥ 12 can be used for differentiation. Through the questionnaire, however, urinary bladder misperceptions and micturition frequency can be well logged

(Bschleipfer 2018)

• Physical examination including:
  • rheumatological findings
  • gynaecological examination
  • proctological examination
• urine status
• urine culture
• to exclude a bladder tumor:
• Sonography (Risler 2008)
  • urine cytology
  • Sonographic determination of residual urine
• Standard assessment such as:
  • Chlamydia
  • Gonorrhoea
  • Mycoplasma
• Exclusion of TBC

(Hegele 2015)

Optional investigations include:

• Sonography of the kidneys
• Cystoscopy with bladder distension and PE to determine the number of activated macrophages and density of nerve fibres in the detrusor
• Excretory urography
• Uroflowmetry
• Potassium chloride test
• Urodynamics
• MRT / or CT of the pelvis

(Hegele 2015)

Uroflowmetry

According to the S2K guideline, uroflowmetry with residual urine determination is recommended for men (Bschleipfer 2018).

Uro-sonography

Uro- sonography should be performed in every case, if necessary with additional examination of the kidneys (Bschleipfer 2018).

Cystoscopy

Cystoscopy can detect Hunner's lesions and other changes in the mucous membranes (Bschleipfer 2018).

In any case, it is recommended to perform a urine examination with test strips and urine culture. Initially, leukocytes or uropathogenic bacteria are often found in the urine (Kasper 2015). In the further course, however, the urine culture is typically inconspicuous.

If sterile leukocyturia or hematuria are present, additional urine cytology should be performed.

(Bschleipfer 2018)

Persistent or intermittent microhematuria is present in approximately 50% of patients.

(Kasper 2015)

In patients with Hunner's lesion, there is interstitial inflammation. Mast cells and granulation tissue are also histologically detectable.

In the remaining 90 % of patients, however, no lesions are found and the bladder mucosa and the interstitium do not show any inflammatory changes (only the above-mentioned glomerulations are detectable).

(Kasper 2015)

However, since no typical histology is present in IC, a biopsy can be omitted (Risler 2008).

• chronic prostatitis (often mistakenly diagnosed in patients with IC)
• overactive bladder (no pain)
• Endometriosis
• endometrial implants
• Irritable bowel syndrome
• Fibromyalgia
• vulvodynia
• chronic urethral syndrome
• Nephrolithiasis
• Bladder cancer

(Kasper 2015)

• Pelvic floor dysfunction
• Hernias
• Scar pain
• malignant diseases of the muscular, skeletal and connective tissue
• chronic inflammatory intestinal diseases
• malignant intestinal diseases
• stenoses of the small or large intestine
• malignant gynaecological diseases
• gynaecological malformations
• ovulation pain
• pelvic varicosis
• genital herpes
• neuralgia
• varicella zoster
• mental disorders
• chronic urinary tract infections

(Bschleipfer 2018)

In the minority of patients who seek medical treatment at an early stage, leukocytes or uropathogenic germs are often initially found in the urine. These are treated accordingly with antibiotics or, in the case of men, an alleged chronic prostatitis is usually treated. However, the above-mentioned symptoms do not improve (Kasper 2015).

A causal therapy for IC does not yet exist (Herold 2021). The aim of the therapy can only be to alleviate the symptoms (Kasper 2015).

Avoidance of stress and hypothermia are recommended. Through bladder training with controlled fluid intake, it is often possible to reduce the frequency and intensity of urination.

The diet should be adapted to any intolerances that may be present.

Due to the long-term course of the disease, patients often develop depression and states of exhaustion, which should be accompanied by appropriate psychotherapy.

Physiotherapy with special pelvic floor physiotherapists can also lead to an improvement in the quality of life.

Treatment with a special vibration plate between 5 - 10 Hz has also led to an improvement in symptoms in some patients.

(Bschleipfer 2018)

Depending on the symptoms, the following internal therapies are available for symptomatic treatment::

• Analgesics
• antihistamines
• Antidepressants
• Antiphlogistics
• muscle relaxant drugs

(Hegele 2015)

• Immunosuppressants

(Bschleipfer 2018)

• 1. analgesics / antiphlogistics

The primary goal should be to relieve the patient of severe pain. NSAIDs, novamine sulfone or opioids may be used.

It must be taken into account that NSRA and opioids release histamine and can therefore intensify the symptoms. An attempt at therapy is nevertheless recommended.

Local anesthetics or certain procedures for regional and conduction anesthesia can also be used for pain that cannot be controlled in any other way.

(Bschleipfer 2018)

• 2. antihistamines

The histamine-2 receptor antagonist cimetidine, for example, was first used in IC by Seshadri et al. in 1994. Improvement occurred in 66% of patients within one month. In a later study, significant improvements also occurred.

Recommended dosage: 2 x 400 mg / d (Bschleipfer 2018).

• Pentosan polysulfate (PPS).

PPS is the only drug approved in Germany for the treatment of IC, provided glomerulations and / or Hunner- lesions are present.

It is synthesized from beech bark (Ehmer 2019) and leads to a repair of the GAG- layer of the urothelium, whereby substances dissolved in the urine (see also "Etiology") can no longer pass the wall of the urothelium (Bschleipfer 2018).

The majority of patients report an improvement in symptoms. However, the first successes are recorded at the earliest after 3 months, occasionally only after 6 - 12 months.

Dosage recommendation: PPS 100 mg 3 x 1 capsule / d

(Ehmer 2019)

• Hydroxyzine can inhibit mast cell activation triggered by neurological stimulation.

Its anticholinergic, anxiolytic and analgesic effects may also lead to the reduction of symptoms.

Dosage recommendation: 25 mg - 75 mg / d.

(Bschleipfer 2018)

• 3. antidepressants

Amitriptyline is a tricyclic antidepressant that inhibits pain transmission in the central nervous system as well as mast cell activation.

Dosage recommendation: Amitriptyline should be given gradually, initially with 10 mg in the evening. However, an onset of action can only be expected from a dose of ≥ 50 mg / d.

(Bschleipfer 2018)

• Mirtazapine

As an alternative to the above-mentioned amitriptyline, the tetracyclic mirtazapine can also be used. However, study results regarding efficacy in IC are not available.

With mirtazapine, a creeping dose of 15 mg in the evening should be started and this should be increased to a maximum of 45 mg/d.

(Bschleipfer 2018)

• 4. muscle relaxants

The alpha- 2- antagonist tizanidine can reduce muscle spasms and muscle spasms that are triggered by the central nervous system. It is usually used together with analgesics.

Dosage recommendation: tizanidine 2 mg - 6 mg / d (Bschleipfer 2018).

• 5. immunosuppressants

Immunosuppressants such as azathioprine, ciclosporin A and methotrexate can also be used in IC. However, the study situation in this regard is very poor, so that in practice immunosuppressants hardly play a role (Bschleipfer 2018).

• Physical therapy

In randomized studies, 1 x weekly physical treatment to relax the pelvic floor has improved symptoms. However, the physical therapist should be informed regarding IC, as the goal of therapy is relaxation and not muscle building.

(Kasper 2015).

If conservative treatment options are unsuccessful, various transurethral procedures are available.

• Hydrodistension (Manski 2019).

This involves dilating the bladder wall with water during a cystoscopy under anesthesia. Up to 40% of patients report a sustained improvement in symptoms for several months afterwards. The stretching of the bladder wall can be repeated if necessary.

(Kasper 2015)

• Intravesical instillation

This involves instilling heparin, chondroitin sulfate, or hyaluronic acid, individually or in combination, into the urinary bladder weekly to improve the permeability of the urothelium by regenerating the GAG (glycosaminoglycan) layer.

(Manski 2019)

• Fulguration

In patients with Hunner's lesions, they can be obliterated with a laser or a snare. Initially, fulguration leads to a significant improvement in pain symptoms (Bschleipfer 2018), but the recurrence rate is high (Manski 2019).

In studies, fulguration in combination with hydrodistension showed greater success in Hunner- type (Bschleipfer 2018).

• Neuromodulation

Neuromodulation is suitable for patients in whom drug treatment is unsuccessful.

A distinction is made between

• Sacral Neuromodulation (SNM):

The treatment success of the only randomized controlled trial showed a 49% success with decrease in pain scale VAS from former 7.9 to 4.0.

• Pudendal neuromodulation (PNM):

Significant randomized controlled trials are not available for PNM. Affected patients who have been treated with pudendal neuromodulation report that they would have implantation again in > 90% of cases.

• Percutaneous tibial nerve stimulation (PTNS):

PTNS has also been used in patients with IC. However, there is little data on efficacy.

To date, it is unclear which patients benefit most from neuromodulation methods.

(Bschleipfer 2018)

Open surgical therapy

As a last resort, open surgical bladder augmentation is available for the treatment of pollakiuria (and also pain reduction according to Bschleipfer 2018) for patients who do not respond to the treatments mentioned so far and have a urinary bladder capacity of < 250 ml (Manski 2019).

Surgical measures that can be considered are the:

• supratrigonal cystectomy, which involves reconstruction of the bladder from intestinal tissue. Studies have shown that 85% of postoperative patients ultimately require cystectomy due to severe pain. Therefore, pain is a contraindication for supratrigonal cystectomy (Bschleipfer 2018).
• Subtrigonal cystectomy (complete bladder augmentation), in which a uretero-intestinal anastomosis is placed (Manski 2019). This method can eliminate pain safely and persistently (Bschleipfer 2018).

Only very rarely does IC heal, and then mainly in the early stages. A characteristic feature of the disease is its undulating course (Hegele 2015).

There is often repeated or even permanent incapacity to work.

In the late stage of the disease, there is a shrinkage of the urinary bladder with a low absorption capacity (Bschleipfer 2018).

Patients with IC have a significantly higher risk of coronary heart disease.

The risk of ischemic insult is also 52% higher than in comparators.

Urinary bladder carcinomas occur in 0.36% of patients and upper urinary tract malignancies in 0.22% (control group: 0.06% and 0.1%, respectively).

(Bschleipfer 2018)

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