Diagnosis and treatment of interstitial cystitis

DIAGNOSIS AND TREATMENT OF INTERSTITIAL CYSTITIS

Terminology: Painful Bladder syndrome/interstitial cystitis (IS)

History: It was first described by Skene in 1887. Typical ulcers seen in 10-50% of patients were first described by Guy L. Hunner at the beginning of the last century. Skene’s terminology was adapted by Bumpus in 1930. In 1949, John Hand published a large series of ISs.

Description: Painful bladder syndrome is a pain that occurs in the bladder region with bladder filling and is a chronic condition with symptoms such as day and night urgency and frequency (frequent urination) seen without infection or other pathologies.

EPIDEMIOLOGY:

Reports on the incidence of IS vary widely; While 10/100,000 in Finland and 8-16/100,000 in the Netherlands are reported, the latest reports from the USA are around 5-6/10,000.

It is 10 times more common in women and is more common in white people.

There are two types, classical and non-ulcerative, and their rates are not clear. In the series recently published from major centers in the USA, the classical IS is around 10-20%.

There is increasing evidence that IS has a genetic component.

PATHOGENESIS:

Although the mechanism of formation is unknown, many theories have been put forward on this subject.

To list some of them;

Infection: No microorganism was found as the cause of IS.

Inflammation: Forms an important part of the picture in classical IS. While pancystitis and perineural lymphocyte and plasma cell infiltration are seen in bladder lesions in these, inflammation is very low in non-ulcer IS.

Mast cell activation: Mast cells are multifunctional immune cells containing highly potent inflammatory mediators such as histamine, serotonin, and cytokines. Many symptoms and signs such as pain, frequent urination, edema, fibrosis and formation of new vessels under the mucosa in classical IS may be related to these factors released from mast cells. In classical IS, 10 times more mast cells are detected in the bladder tissue compared to the control group. In non-ulcer IS, the mast cell count is normal or slightly elevated.

Mucosal dysfunction/glycosaminoglycan (GAG) layer defect: All patients with IS have some degree of bladder mucosa fragility, and fissures or tears occur in the bladder mucosa when stretched with urine. While mucosal separation and gross defects in the mucosa are characteristic in classical IS, many superficial defects (glomerulation) are also seen in some non-ulcer IS patients after bladder stretching. According to Parson and Mulholland, who put forward this hypothesis, the GAG ​​layer defect causes submucosal nerve endings to come into contact with chemicals such as nontoxic potassium (K) and urea in the urine. Loss of this protective mucin layer probably causes patients with IS to have a more painful response to urinary solutes (such as K).

Autoimmune mechanisms: Although there are many studies on autoantibodies in patients with IS, no specific finding could be obtained.

Toxic agents: Toxic compounds in urine can cause bladder injury in IS. One hypothesis is that low molecular weight, heat sensitive, cationic urinary components may exert a cytotoxic effect.

Hypoxia: A decrease in microvessel density was observed under the mucosa. In a recent study, it was found that when the bladder is full, the blood supply to the bladder decreases in IS, but on the contrary, it increases in the controls.

Recent studies suggest that IS may occur as a result of a complex interaction between the nervous system, immune and endocrine systems.

PATHOLOGY:

There is no definitive diagnostic finding for IS in biopsy materials.

Mast cell infiltration is evident in the bladder wall and mucosa in approximately 1/3 of the patients and especially in classical type IS (ulcerative type).

In light microscopy, the mucosa is thin (2-4 folds instead of 6-7 folds), showing separation in some areas or not at all. These findings are consistent with a dysfunctional epithelium.
Infiltration of mononuclear and chronic inflammatory cells (pancystitis) is seen in the connective tissue under the mucosa.
According to one hypothesis, a small fibrotic bladder occurs as a result of the progression of the disease, but there is no information to support this. In the studies, scar tissue could not be detected except for the old biopsy sites taken in large numbers.
In cystectomies performed for IS, only epithelium, few blood vessels and muscle fibers remained in the bladder. Perivesical adipose tissue was severely decreased.
Biopsy is useless because it has no diagnostic value, but in some cases it can be done for the diagnosis of Carcinoma in situ (a superficial type of cancer).
SYMPTOMS:

The main symptoms are pelvic pain with frequency (frequent urination) and urgency (sudden urgency). Pelvic pain is especially pronounced when the bladder is full and subsides when it empties. In some patients, there may be no urgency besides pain.

In a study of 200 patients, approximately 15% of patients had little or no bladder pain, while 85% had significant pain. What is important here is whether the pain originates from the bladder, which can be understood by the relationship of pain with bladder fullness. Although this is useful information, the pain in some patients may not be affected by the bladder volume.

Bladder pain in IS can be felt in the pelvis, especially in the bladder area, perineum, vagina, lower back, and even inside the thigh. In men, it can also be in the scrotum. 1/3 of the patients have dysuria (burning while urinating).

Nocturia (nocturnal urination) is variable, usually 90% of patients have at least 1-2 urination at night, some patients may not. Nocturia increases with the duration and severity of the disease.

Patients urinate an average of 16 times a day, the minimum number of voidings/day for diagnostic purposes is considered to be 8. The average volume is 75 ml each time.

Constipation, irritable bowel syndrome, depression, fibromyalgia, musculoskeletal pain, allergies or migraine may also be seen more frequently in these patients.

85-90% of patients are female. In the majority of sexually active women (75%), symptoms are associated with sexual contact. The increase in symptoms may occur during, immediately after, or within 24 hours of sexual intercourse and may last for days. There is a similar relationship with the menstrual cycle. Due to these relationships and pelvic pain, patients with the diagnosis of endometriosis may undergo unnecessary hormonal therapy and even hysterectomy, but the pain does not change.

NIDDK Criteria (28-29 August 1987): It contains important criteria sought when making a diagnosis today.

Automatic diagnostic criteria

– Hunner’s ulcer (classic ulcer type)

Positive Factors

– Relief of pain in bladder filling when empty

– Pain (bladder area, pelvic, urethral, ​​vaginal, perineal)

– Small bleeding foci called glomerulation in endoscopy

– Decreased compliance in cystometry (immediate rise in intravesical pressure even with a small amount of fluid given to the bladder)

Automatic exclusion criteria

-< 18 years

-Bening or malignant bladder tumor

-Radiation cystitis

-Tuberculosis cystitis

-Bacterial cystitis

-vaginitis

-Cyclophosphamide cystitis

-Symptomatic urethral diverticulum

-Uterus, cervix, vagina and urethra cancers

-Active herpes

– Bladder and lower ureteral stones

Urinary frequency while awake is less than 5 times in 12 hours

– Less than 2 urinations at night

Relief of symptoms with antibiotics, urinary antiseptics, urinary analgesics

– Onset less than 12 months

– Involuntary bladder contractions (urodynamics)

– Bladder capacity greater than 400 cc

Differential diagnosis:

Bladder cancer, bladder or urinary system infection, cystocele/rectocele, endometriosis, urinary system stones, neurological disorders, pelvic floor dysfunction, sexually transmitted infections, urethral diverticula, pelvic organ prolapse, vaginal infections.

DIAGNOSIS:

The patient’s history is very important in considering IS. In particular, the character of the pain is the key symptom. The duration of the disease is important in differentiating IS from the milder form of urgency-frequency syndrome (UFS). A diagnosis of IS is more likely if symptoms have been persistent for at least 6 months.

Voiding diary: The number of voids per day and the mean volume are derived from 2-day patient records. The average number of voids per day is 16 and the average volume is 75 ml. It is a useful method in diagnosing IS.

Physical Examination: Usually nonspecific. On pelvic examination, there may be tenderness in the anterior vaginal wall and bladder area, and pelvic floor spasm.

There should be no bacteria in the urine analysis, leukocytes and erythrocytes are not seen in most of them. Urine cytology can be sent to differentiate between cancer and cancer in situ. In those with hematuria (blood in the urine), a full genitourinary investigation should be performed to rule out malignancies (IVP, US, cystoscopy, cytology).

Three important tests are helpful in demonstrating the diagnosis of IS, two of which are written question-and-answer questionnaires—the pelvic pain and urgency/frequency (PUF) patient symptom scale and the O’Leary Sant IS symptom index—and the third is the intravesical potassium sensitivity test (PDT). evaluates epithelial permeability.

1-PUF Symptom Scale: This 8-item scale is important in measuring the presence and severity of symptoms (symptom score) and evaluating how much the symptoms bother patients (bother score). The sum of these two scores gives the total score. High symptom score, bother score, and high total score (15+) strongly suggest IS.

2-O’Leary Sant IS Symptom Index: It is a non-invasive question-answer test in the diagnosis of IS and can be used to evaluate patients’ IS symptoms and treatment outcomes. This index includes 4 main items that measure sudden urgency, frequent urination, night urination, pain or burning. The high total score obtained by adding the scores obtained from the answers to the questions helps in making the diagnosis.

3-Potassium Sensitivity Test (PDT): Potassium chloride (KCL) is not absorbed when given to a normal bladder, it does not cause sudden squeezing and pain, but it diffuses between the mucous cells in patients with IS, which is believed to have impaired mucosal permeability, and stimulates the nerve endings and causes a severe, sudden squeezing sensation and pain. / or cause pain. First, 100 cc of sterile saline is given to the bladder to evaluate the pain, after emptying, 60 cc of saline + 40 cc of KCL (1meq/ml) is given and the pain is re-evaluated. The test is considered positive when there is a significant increase in pain.

Cystoscopy: It is performed under general or regional anesthesia because it is not possible to perform hydrodistension (excessive stretching of the bladder with serum) during cystoscopy without anesthesia in painful bladders. Cystoscopy is performed in two stages. In the first stage, initial monitoring is performed and urine is taken for cytology and tuberculosis culture if necessary. True Hunner’s ulcer (classic ulcerative type) patches can be seen in this first visual examination. These are velvety red patches very similar to superficial carcinomas, not true ulcers and 6-8% rate (Classic IS). In non-ulcer IS, the bladder mucosa appears normal in this first observation. The second step is hydrodistension to see glomerulations, which in 60% of the patients regresses the symptoms. With a water pressure of 80-100 cm, the bladder is slowly filled with saline (SF) as much as possible under anesthesia. Meanwhile, the urethra meatus is closed with a finger to prevent fluid escape. A few minutes after the fluid flow stops, the bladder is emptied and its volume is measured. After two hydrodilations, diffuse glomerulations in the bladder (at least 10-20 in each quadrant) is important in diagnosis. The capacity of a normal woman’s bladder under anesthesia is 1000 cc, while it is <850 ml in patients with IS and the mean in patients with moderate and severe IC. It is 550-650 ml. Although the mechanism by which hydrodistension relieves the symptoms is not known, in 90% of the patients, when they wake up from anesthesia, the pain increases but decreases in 2-3 weeks and narcotic analgesics may be required during this period. It is appropriate to administer 2% lidocaine 10 ml into the bladder before waking up after distension and to prescribe analgesics (narcotic) at discharge. Biopsy is performed at the last stage of cystoscopy, biopsy should not be taken before hydrodistension to avoid bladder rupture during hydrodistension. Biopsy is not diagnostic of superficial cancer and tuberculous cystitis. It can be useful in excluding diseases such as An increase in mast cells and other inflammatory cells and a thin mucosa can be seen on pathological examination. In non-ulcer patients, chronic inflammation findings are minimal.

TREATMENT:

Medical Treatments:

Analgesics (Painkillers): When the dominant symptom is pain, frequently used analgesics, especially non-steroidal anti-inflammatory ones, are preferred by patients, but the results are not very promising because the pain in IS is visceral type and does not respond well to this type of drugs. The use of opioids (narcotic analgesics) by patients with severe IS is not uncommon, but it should be noted that opioids stimulate mast cell secretions.
Antidepressants: Relief of IS symptoms has been reported with tricyclic antidepressants such as amitriptyline and imipramine.
Antihistamines: Many allergic problems, including asthma, have been found in IS patients. H1 and H2 receptor blockers were used to inactivate histamine released from mast cells, which is thought to play a role in IS. Hydroxyzine (Atarax) is a histamine-H1 receptor antagonist, starting with 25 mg at night and increasing to 50 or even 75 mg/day. Its important side effects are sedation and fatigue.
Prostaglandin: Misoprostol is a prostaglandin that regulates many immunological cascades, it has been used at a dose of 300 microgr./day in IS, positive results have been obtained, but the side-effect rate is around 64%.
L-Arginine: Reduction in IS symptoms has been reported as a result of oral treatment with L-Arginine, which is involved in nitric acid synthesis.
Corticosteroids: Since inflammation plays an important role in this disease, corticosteroids have been tried, with both promising and discouraging reports. The excess of side effects limits its use.
Gabapentin: Gabapentin, a new antiepileptic drug, is also used as an additional drug in painful diseases, reducing the need for opioids.
Immunosuppressant (immunosuppressant) agents: Azathioprine (50-100 mg/g) has been reported to reduce pain and urinary frequency in more than half of the patients, but the value of this therapy in IS is not clear since side effects have not been reported and there are no controlled studies. Recently, good results have been obtained with cyclosporin and methotrexate in pain, but its effect on urgency and frequent urination has been limited.
Suplatast Tosilate (IPD-1151T): It is an oral immunoregulatory agent that suppresses allergic events controlled by helper-T cells. It reduces Ig-E production and eosinophilic inflammation. In 14 IS patients, 13 of whom had classic IS, 300 mg/g was used for one year and a significant increase in bladder capacity and a decrease in symptoms were reported in patients. Although there is no obvious side effect, comparative controlled studies are needed.
Quercetin: It has antioxidant, cell protective and anti-inflammatory activities, and also inhibits mast cell secretion and proliferation. It has been used in pelvic pain syndrome such as IS and chronic prostatitis and has provided a certain improvement. Recently, the combination of chondroidin sulphate and quercetin obtained from shark cartilage increase the effects of each other on mast cell inhibition. This combination is patented under the name Algonot-Plus and is widely used in the USA.
Sodium pentosanpolysulphate (PPS; ELMİRON): It is the only agent approved by the FDA (American Food and Drug Administration) in the oral treatment of IS. While it provides subjective improvement in pain, sudden urgency and frequent urination, it is ineffective in night urination. It has been shown to be effective in chronic non-bacterial prostatitis. It appears to be more effective in classical IS than non-ulcer IS. It is thought that PPS replaces the defect in the GAG ​​layer. Another hypothesis is that it inhibits mast cell activation. 100 mg X3 or 150-200 mg taken twice a day between meals. In mild cases, the effect occurs after 6-10 weeks, while in severe cases it may take 6-12 months. In severe IS cases, dose increase may be required and it can be increased to 200 mg X8/day. In order to obtain a good response, the drug should not be discontinued before 9-12 months as ineffective. Continuous use of PPS for years provides long-term disease control. Long-term success in this way has not been previously reported with any agent other than intravesical heparin. It does not have serious side effects, there may be side effects such as nausea and vomiting, and it is recommended to take the drug with a light meal. Hair loss may occur at a rate of 1-2%, and it is often reversible even if the treatment is continued.
TREATMENTS APPLIED IN THE BLADDER: These applications provide high drug concentration with less systemic side effects on the target organ. They have reservations about the need for intermittent bladder catheterization in these treatments, which is painful in patients with IS, increases the risk of infection and increases the cost. Main agents administered intra-bladder:

Local Anesthetics: Lidocaine has a local anesthetic effect on the mucosa, but its absorption is poor.
Sodium pentosanpolysulphate (PPS; ELMİRON): It has been used to be given into the bladder due to its poor bioavailability in oral use. When 300 mg of PPS was applied twice a week in 50 ml of saline (SF.), relief of symptoms was found in 40% of the patients in 3 months and in 80% of patients in 18 months.
Heparin: Intra-bladder heparin is one of the most widely used treatments for IS. It is thought that heparin, as a coating agent, mimics the protective effect of the GAG ​​layer in the mucosa and has an inhibitory effect on mast cells in the bladder. There are different applications regarding the dosage 10.000 units10 ml SF. With the application 3 times a week, more than half of the patients achieved relief in symptoms in 3 months, and positive responses were obtained with maintenance therapy for more than one year. There are those who apply it as a dose of 20,000-40,000 U/20 ml of SF. Treatment should not be discontinued before 12 months, as the best effect occurs in 1-2 years and long-term treatment is recommended in cases of moderate to severe IS that respond to treatment. In long-term treatments, patients should be followed up with PTZ and PPTZ.
Hyaluronic Acid: In recent publications, the high level of hyaluronic acid in the urine of patients with IS was interpreted as GAG defect, and intra-vesical glycoseaminoglycan sodium hyaluronate (Cystistat) was administered to these patients. As a result of 4 weeks, 40 mg once a week, 56% response, and then monthly application, 70% response was obtained at 14 weeks, but the response rate decreased after 6 months.
Dimetyl sulphoxide (DMSO): It is a water-soluble chemical substance that penetrates cell membranes and is claimed to have analgesic, anti-inflammatory, collagen-destroying and muscle relaxant effects. It also destroys intracellular hydroxy(OH) radicals, which are believed to play an important role in triggering inflammatory events. It has become a standard treatment today. 50 ml of 50% DMSO in the bladder 5-10 minutes. It is kept, not left longer because it is quickly absorbed. Since a good clinical response is achieved in 2-3 months, 6-8 weeks of treatment is first applied to evaluate the patient’s response, and in moderate and severe cases, an additional 4-6 weeks every 2 weeks may be required. Importantly, once DMSO is discontinued, the patient is likely to become resistant to its use. Some patients may experience exacerbation of symptoms when DMSO is administered into the bladder, but in these patients DMSO can treat quite effectively. In these patients, 2% lidocaine gel can be given to the bladder 15 minutes before. DMSO may cause pigmented deposits in the eye lens, and eye examination should be performed during treatment. It should not be applied during urinary infection and in the early period after biopsy.
Bacillus-Calmette –Guerin(BCG): This substance, which is used as a tuberculosis vaccine, was used in 30 IS patients for 6 weeks in a study conducted in 1997 and a 60% response was obtained. On the other hand, in another study comparing BCG and DMSO, adequate results were not obtained with BCG.
Clorpactin: It is an acid derivative of Buffered HCl and was used in the treatment of tuberculous cystitis, then it was used in the treatment of IS 50 years ago. First, mucosal destruction occurs and this is followed by reconstruction with intact tissue. It has been reported that 0.4% solution provides effective and long-term relief with intravesical administration. Since the procedure is painful, it should be performed under anesthesia. After the treatment, pain and dysuria worsen and continue for days. Monthly and weekly treatment intervals have been suggested, with response rates of 50-70% over a 6-12 month period. It is contraindicated after vesicoureteral reflux and new biopsy.
Vanilloid Group: Vanilloids inhibit sensory (sensory) neurons. Resiniferatoxin (RTX) is a strong analog of capsaicin, a red pepper extract. Intra-bladder administration gives less pain. reduced nighttime urination by around 50%.
Botox: Recently, studies have been carried out with botox, which is a neurotoxin. Especially promising results have been obtained in patients with interstitial cystitis associated with overactive bladder or bladder spasm. When the effect lasts for 3-6 months, it should be repeated during this period.
INTERVENTIONAL TREATMENTS:

Hydrodistention of the bladder: Although it is frequently used in the treatment of IS, there is not enough information to prove its scientific justification. It is more of a diagnostic tool but has a limited therapeutic role.

Electro motivated drug administration (EMDA): It increases the passage of ionized drugs into the tissue with a technique called iontophoresis. When adapted to the bladder, an anode is placed through the urethra and a skin cathode is placed in the bladder region. In limited studies, EMDA with lidocaine 1.5+1/100.000% epinephrine, lidocaine+ dexamethasone, lidocain+dexamethasone+heparine combinations have been used. There are no controlled studies on this subject yet and EMDA treatment is an expensive method.

Transurethral Resection (TUR), coagulation and transurethral laser: It aims at resection of Hunner’s ulcers seen in classical type in the bladder with electrocautery, this procedure is performed with a closed method by entering through the urethra (TUR). Relief in symptoms often results in recurrence within a year, and efficacy is not superior to non-surgical methods.

Neodymium-YAG: transurethral application of laser can be considered as an alternative to TUR in the endoscopic treatment of IS. Endourological methods such as TUR or laser (closed operations) cannot be applied in non-ulcer IS. Neuromodulation: This method, which has been approved by the FDA especially for overactive bladder and non-obstructive urinary retention, is used in IS. Successful results have been obtained, especially in patients with IC who have sudden urgency and frequent urination rather than pain. However, recent studies are promising in patients with predominant pain.

Neuro modulation: This method, which has been FDA approved especially for overactive bladder and non-obstructive urinary retention, is used in IS. Successful results have been obtained, especially in patients with IC who have sudden urgency and frequent urination rather than pain. However, recent studies are promising in patients with predominant pain.

Alternative and complementary therapies:

Bladder training: With timed voiding, controlled fluid intake, pelvic floor muscle training in selected patients with IS, voiding intervals could be extended and the average number of voidings per day was reduced to 9.
Dietary Restriction: There is an extensive list of things to avoid.
– Many fruits, especially citrus fruits (except melon, watermelon, peach)

– Onions, broad beans, fried foods.

– Yogurt, chocolate, sour cream, aged cheeses

– Rye bread, yeast breads

– Most of the nuts (except almonds and pine nuts)

– Canned, cured and cured meats and fish, caviar, chicken livers, meats containing nitrates and nitrites.

– Alcoholic beverages; beer, wine, carbonated drinks, tea, coffee

– Mayonnaise, ketchup, mustard, soy sauce, vinegar and spicy food.

– Preservatives in food; sweeteners such as benzol alcohol, citric acid, mono sodium glutamate and aspartate, saccharin.

Surgical Treatments: If symptoms are not relieved despite all methods, removal of the patient’s bladder should be considered as an option. Augmentation operations without cystectomy (removal of the bladder) are not suitable treatments. In addition to operations that protect the area called trigon in the bladder outlet, there are also techniques that remove the entire bladder by taking this place. Artificial bladders are created by using different bowel segments (small or large intestine) instead of the removed bladder. In 40-50% of the patients, pocket pain may occur 6-36 months after the operation. Heparin 10.000 U and/or PPS can be used again in these patients. Since there is not enough emptying and the patient has to insert a catheter several times a day, it is a frequently preferred method to open the urinary tract called ileal conduit to the abdominal skin through a short intestinal segment.

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