Bladder Pain Syndrome/Interstitial Cystitis: A Large but Heterogeneous Field in Functional Urology

Fig. 4.1

Classic interstitial cystitis with Hunner lesion (bladder pain syndrome 3C), distension during anaesthesia provoking the lesion to split with petechial bleeding in a waterfall manner from the lesion site and the mucosal margins

Over the years, controversy has developed as to the prevalence and even the actual existence of the Hunner lesion and some urologists maintain that they are rare, or do not exist, and the fact that they rarely detect them confirms this false impression. The distribution varies from 5 to 50 % of cases with BPS in various populations, centres and series. Detection is certainly a matter of attention and training though, and a rigorous routine increases detection. Supplementary techniques might be helpful to increase detection rate, like the narrow band imaging method.

It is important that these bladder lesions are identified as soon as possible since treatment options and responses differ considerably between the classic Hunner type of IC and other phenotypes.

Treatment

How to Select an Efficacious Treatment?

There are obvious dilemmas when trying to make a wise decision on therapy in BPS. A great variety of solutions have been tried, essentially on a trial-and-error basis. Many methods have been discarded; a few have stood the test of time. Correct classification and phenotyping of the heterogenic group of conditions that may result in pelvic pain is crucial for a good outcome of treatment, while in reality methods to reliably identify phenotypes are insufficient. The significance of this problem is very important but still not generally acknowledged. This is in contrast to a strive in urologic oncology to improve phenotyping and identify critical characteristics to optimize treatments. The fact is that, although the more inclusive attitude of later years has drawn a desirable attention to the entire spectrum of disorders resulting in bladder pain, the wish to include all of them into simple and handy entities has resulted in much scientific and clinical confusion. Ten years ago, a scientific association was founded, with one of its objectives to draw attention to the diagnostic and therapeutic problems in BPS/IC, denominated the European Society for the Study of Interstitial Cystitis (ESSIC), nowadays the International Association for the Study of Bladder Pain Syndrome. They suggested a standard on how to examine and classify patients with bladder pain, addressed the problem of so-called confusable diseases (Tables 4.1 and 4.2), stressed the importance of phenotyping and updated the terminology.

Table 4.1

Confusable diseases for bladder pain syndrome

Carcinoma and carcinoma in situ

Infection with

Common intestinal bacteria

Mycobacterium tuberculosis

Chlamydia trachomatis

Ureaplasma urealyticum

Mycoplasma hominis

Mycoplasma genitalium

Corynebacterium urealyticum

Candida species

Herpes simplex

Human papilloma virus

Radiation

Chemotherapy including immunotherapy with cyclophosphamide

Anti-inflammatory therapy with tiaprofenic acid

Bladder neck obstruction and neurogenic outlet obstruction

Bladder stone

Lower ureteric stone

Urethral diverticulum

Endometriosis

Vaginal candidiasis

Cervical, uterine and ovarian cancer

Incomplete bladder emptying (retention)

Overactive bladder

Prostate cancer

Benign prostatic obstruction

Chronic bacterial prostatitis

Chronic nonbacterial prostatitis

Pudendal nerve entrapment

Pelvic floor muscle related pain

van de Merwe JP, Nordling J, Bouchelouche P, Bouchelouche K, Cervigni M, Daha LK, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol. 2008;53(1):60–7

From a therapeutic standpoint, one entity stands out as especially important to identify. The so-called classic IC (Hunner disease, ESSIC type 3C) is a specific and well-defined entity and fulfils the requirements of the original denomination “interstitial cystitis”: There are histological signs of a marked inflammation in the bladder submucosa and musculature (the bladder interstitium) together with typical cystoscopic features. Evidence is accumulating on unique and outstanding features of this entity, with great implications on treatment.

Table 4.2

Cystoscopy with hydrodistension

	Not done	Normal	Glomerulations^a	Hunner’s lesion^b
Biopsy
Not done	XX	1X	2X	3X
Normal	XA	1A	2A	3A
Inconclusive	XB	1B	2B	3B
Positive^c	XC	1C	2C	3C

Adapted from van de Merwe JP, Nordling J, Bouchelouche P, Bouchelouche K, Cervigni M, Daha LK, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol. 2008;53(1):60–7

^aCystoscopy: glomerulations grade 2–3

^bWith or without glomerulations

^cHistology showing inflammatory infiltrates and/or detrusor mastocytosis and/or granulation tissue and/or intrafascicular fibrosis

Conservative Treatment

In the pelvic area, abnormal activity in the pelvic floor musculature with possible involvement of joints, ligaments, fasciae and viscera may cause adverse interactions. Therapeutic approaches include breath work, biofeedback techniques and soft tissue manipulations to aid in muscle relaxation of the pelvic floor. Especially important seems the identification of trigger points, frequently found in, e.g. the pubococcygeus, piriformis, external oblique, rectus abdominis, hip adductors and gluteus medius muscles. A number of soft tissue manipulative but also invasive techniques are available to release symptoms related to soft tissue pathology in BPS/IC, but presently, this is an underused asset in the treatment armamentarium of this disease complex.

A recent example is a report on myofascial treatments, a multicentre trial in the US, involving numerous prestigious authors. Eleven clinical centres were included in a randomised study of 10 scheduled treatments compared to global therapeutic massage. A total of 81 women were randomised to the two treatment groups. They had similar symptoms at baseline. Subjects had demonstrable pelvic floor tenderness on physical examination and no more than 3 years’ symptom duration. The primary outcome was the proportion of responders who were improved in overall symptoms compared to baseline on a 7-point global response assessment scale. Secondary outcomes included ratings for pain, urgency and frequency, the O’Leary-Sant IC Symptom and Problem Index and reports of adverse events. The response rate was 59 % in the myofascial physical therapy group vs 26 % in the global therapeutic massage group, a difference found to be significant. Pain, urgency and frequency ratings, and O’Leary-Sant IC Symptom and Problem Index decreased in both groups during follow-up, not significantly different between the groups though. Pain was the most common adverse event, occurring at similar rates in both groups. No serious adverse events were reported.

Per Oral Drugs

Pentosan polysulphate sodium (PPS), a highly sulphated mucopolysaccharide, is the only oral therapy approved by the US Food and Drug Administration, recommended in the AUA guidelines. It also has a high degree of recommendation according to the EAU guidelines, level of evidence 1a; grade of recommendation A. PPS has efficacy in a subset of 50 % of patients, by time dropping to 30 % of those initially treated. As a rule, it will take up to 6 months before benefit is experienced. The usual dosage is 150–300 mg daily, divided in two or three doses. Treatment responses are rather duration dependent than dose dependent. The safety and efficacy of oral pentosan polysulphate sodium (PPS), hydroxyzine and the combination of the two were evaluated in a pilot randomised clinical trial. A nonsignificant trend was seen in the PPS treatment groups as compared to no PPS. The low global response rates for PPS (and hydroxyzine) suggested that neither provided benefit for the majority of patients with BPS/IC. However, a serious limitation of the study was low numbers of subjects for follow-up. With reference to phenotyping, it can be noted that in an early, open study, patients with the classic Hunner type of disease seemed to be better responders than non-Hunner patients.

Systemic cortisone has also a long tradition; anti-inflammatory treatment using cortisone has been used, although not as a standard option, in BPS/IC for more than four decades. Efficacy has been demonstrated even more recently in the classic Hunner type of disease, but since the side effects of chronic steroid treatment can be very serious, it is difficult to justify systemic, long-term use. For this reason, the EAU guidelines do not recommend systemic cortisone in BPS/IC.

Amitriptyline, a tricyclic antidepressant, has a number of properties like blockade of acetylcholine receptors, inhibition of reuptake of released serotonin and noradrenalin, and blockade of histamine H1 receptors. This drug is standard in chronic pain treatment and can be used alone or in combination with other treatments. It is used in doses starting at 10 mg daily that are slowly increased over several weeks to up to 50–75 mg daily as tolerated. It tends to diminish pain, increase bladder capacity, block the actions of histamine, act as a mild antimuscarinic, and aid sleep. It has a high degree of recommendation according to the EAU guidelines, level of evidence 1a, and grade of recommendation A.

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