Methods and incentives for the early diagnosis of bladder pain syndrome/interstitial cystitis, "Beyond the Abstract," by Magnus Fall and Ralph Peeker

BERKELEY, CA ( - Bladder pain syndrome very often has a devastating effect on patients’ physical, professional, and personal lives. Generally, recognition of this complex problem is hampered by insufficient expertise in the medical community, and the diagnosis is often delayed by several years -- usually preceded by multiple medical consultations and various treatment attempts.

The conception of this disease complex has transformed dramatically since a deep-going inflammatory disease of the urinary bladder called “interstitial cystitis” (IC), with bladder pain, was first described about one hundred years ago.[1, 2] Depending on a variety of observations and considerations of diagnostic definitions, IC came to represent a symptom complex with varying contents, but still with an unchanged denomination. Gradually, the content of this diagnosis became quite vague and variable. Recently, several organizations have placed increasing focus on this problem and have come to include all patients with bladder pain, the umbrella terms painful bladder syndrome, or, later, bladder pain syndrome (BPS) were suggested, now incorporating the classic conception of IC as a well-defined phenotype.[3, 4, 5]

The condition is suspected when patients’ report typical symptoms. The classic description is pain supra-pubically, sometimes radiating towards the groin, vagina, or lower back, increasing during bladder filling. Very typically, pain is relieved by micturition, indicating involvement of volume-dependent bladder afferents. Subsequently, the description has become wider, though. According to current understanding, pain can be felt to be in the bladder, or rather in the area that the patient perceives as the bladder, or in the abdomen and pelvis. Other descriptions of sensations are ‘pressure,’ ‘burning,’ ‘sharp,’ and ‘discomfort.’ Although typically pain is felt in the supra-pubic region, it is not always limited to this area; it can be referred to locations throughout the pelvis, including the urethra, vagina, lower abdomen, lower back, medial aspect of the thigh, and the inguinal area, in any combination. Consequently, it is not always obvious that the pain is coming from the bladder due to these wide referral areas. There is an ongoing debate on whether urgency symptoms qualify for inclusion in the BPS/IC complex, a debate which is not resolved (although the view of the present authors is that including qualities of urgency while excluding pain would make the target diagnosis too wide, bringing together conditions with too different pathophysiologies).

Another debate is on the value and need of cystoscopy. One very important argument is that presently it is the way to detect the classic Hunner type of disease. This is a specific entity yielding much better options for symptomatic cure compared to other BPS phenotypes, and with other treatment requirements.[6, 7] In this context, it should be emphasized that the so called Hunner’s ‘‘ulcer’’ is not a persistent chronic ulcer but rather a distinctive inflammatory lesion with characteristic central fragility, presenting a deep rupture through the mucosa and submucosa when provoked by bladder distension.[5] Many urologists maintain that Hunner's lesions 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 per cent of cases with BPS in various populations, centers, and series.[8, 9, 10, 11, 12] Certainly, detection is a matter of attention and training.

During recent decades, understanding of the properties of various cell systems has developed dramatically, and, moreover, the diagnosis with standard staining procedures and light microscopy can now be enhanced with immunohistochemistry and even more sophisticated and sensitive amplification techniques such as polymerase chain reaction (PCR) in situ and various blot and array techniques. Histopathologic examination of adequate biopsy material is of decisive importance to exclude confusable bladder diseases[5] and to reach a dependable differential diagnosis as to main BPS phenotypes.[13] A limitation in clinical practice is that reliable assessment calls for a specialized pathologist. For research purposes, investigations of various cellular features are mandatory in the search for aetiology and pathogenesis in BPS phenotypes.

At this stage, markers have a limited role in the detection and diagnosis of BPS/IC but hold promise for the future. Having access to an accurate urine or blood biomarker for the diagnosis of BPS would be a tremendous advantage. However, proper biomarker discovery requires detailed knowledge of the disease, including definitions, disease phenotypes, as well as the local and systemic responses. Such knowledge is, to a great extent, lacking in BPS. In addition, since BPS is no doubt a heterogenic syndrome, it is unlikely that a single biomarker could cover the entire spectrum. Presently, the most promising marker candidate seems to be APF,[14] although at this stage there is not enough evidence to support APF as a generally useful diagnostic tool. Another observation of immediate practical importance as to differentiation of phenotypes is that determination of intravesical evaporation of nitric oxide (NO) seems to provide a reliable means to differentiate the classic Hunner type from other BPS presentations.[15]

BPS may be part of a more general pain syndrome with various expressions. It is believed that changes occur within the CNS throughout the whole neuraxis and that central changes may also be responsible for some of the psychological changes that quite importantly modify pain mechanisms. Core muscles, e.g., the pelvic floor and adjacent muscles, may become hyperalgesic, with multiple trigger points. Other organs may also become sensitized, like the bowel with irritable bowel symptoms. Fibromyalgia and chronic fatigue syndrome are more common in patients with BPS/IC, too.[16] There have been many hypotheses to explain these associations, like neuronal sensitization in spinal segments of common projection, or immunologic abnormalities, or that the disease progresses from an organ-centered condition to a regional, and finally a systemic pain syndrome. The pattern of associated disorders is not unique for BPS; in this respect there are similarities with other pelvic pain syndromes. It is not unusual that the situation of an individual patient is complex. When standard, organ-centered trials of treatment fail, early involvement of the multidisciplinary team is vital. If consultation is delayed, hypothetically there is a risk that CNS patterns of pain processing will be permanently changed, resulting in a chronic pain condition.

The diagnostic work and therapeutic efforts in BPS include many challenges. Already the initial position entails conflicts: Chronic pain has to be regarded as a disease in its own right, and calls for attention accordingly. That includes multidisciplinary care, where the way of looking at the matter differs from the organ-centered view. On the other hand, the first goal of therapy is causal treatment and cure, if possible, or at least exclusion of serious diseases. That requires adequate clinical investigation, including relevant phenotyping. This is an everyday dilemma in consultation with the patient with BPS: too much or too little attention to the clinical work-up may ruin the outcome.


  1. Hunner GL. Elusive ulcer of the bladder: further notes on a rare type of bladder ulcer with report of 25 cases. Am J Obstet. 1918;78:374-95.
  2. Skene AJC. Diseases of Bladder and Urethra in Women. New York: Wm Wood; 1887. 167 p.
  3. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology in lower urinary tract function. Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodynam. 2002;21:167-78.
  4. Fall M, Baranowski AP, Fowler CJ, Lepinard V, Malone-Lee JG, Messelink EJ, et al. EAU guidelines on chronic pelvic pain. Eur Urol. 2004;46(6):681-9.
  5. 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.
  6. Fall M, Johansson SL, Aldenborg F. Chronic interstitial cystitis: a heterogeneous syndrome. J Urol. 1987;137:35-8.
  7. Peeker R, Fall M. Treatment guidelines for classic and non-ulcer interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct 2000;11(1):23-32.
  8. Jones CA, Harris M, Nyberg L. Prevalence of interstitial cystitis in the United States. J Urol. 1994;151:423.
  9. Logadottir Y, Fall M, Kåbjörn-Gustafsson C, Peeker R. Clinical characteristics differ considerably between phenotypes of bladder pain syndrome/interstitial cystitis. Scand J Urol Nephrol 2012;46(5):365-70.
  10. Meares E, Jr. Interstitial cystitis--1987. Urology. 1987;29(4 Suppl):46-8.
  11. Peeker R, Fall M. Towards a precise definition of interstitial cystitis: further evidence of differences in classic and nonulcer disease. J Urol. 2002;167:2470-2.
  12. Webster GD, Galloway N. Surgical treatment of interstitial cystitis. Indications, techniques, and results. Urology. 1987;29(4 Suppl):34-9.
  13. Johansson SL, Fall M. Clinical features and spectrum of light microscopic changes in interstitial cystitis. J Urol. 1990;143(6):1118-24.
  14. Keay S, Zhang C, Chai T, Warren J, Koch K, Grkovic D, et al. Antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor in men with interstitial cystitis versus chronic pelvic pain syndrome. Urology 2004;63(1):22-6.
  15. Logadottir Y, Ehren I, Fall M, Wiklund NP, Peeker R. Intravesical Nitric Oxide Production Discriminates Between Classic and Nonulcer Interstitial Cystitis. J Urol. 2004;171:1148-51.
  16. Buffington C. Comorbidity of interstitial cystitis with other unexplained clinical conditions. J Urol. 2004;172:1242-8.


Written by:
Magnus Fall and Ralph Peeker as part of Beyond the Abstract on This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

University of Gothenburg, Sahlgrens University Hospital, Department of Urology, Göteborg, SE-41345, Sweden

Methods and incentives for the early diagnosis of bladder pain syndrome/interstitial cystitis - Abstract

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