and Related Disorders
Roc McCarthy, D.O.
Painful Bladder Syndrome
n Painful bladder syndrome/interstitial cystitis (PBS/IC) is a condition
diagnosed on a clinical basis and requiring a high index of suspicion by
n Simply put, it should be considered in the differential diagnosis of the
patient who presents with chronic pelvic pain that is often exacerbated
by bladder filling and associated with urinary frequency.
n The term Interstitial cystitis, was not at all descriptive of the clinical
syndrome or the pathologic findings in many cases leading to the
current effort to reconsider the name of the disorder and even the way it
is positioned in the medical spectrum
n PBS/IC encompasses a major portion of the "painful bladder"
-including bladder and/or urethral and/or pelvic pain, irritative
voiding symptoms (urgency, frequency, nocturia, dysuria), and
n Painful bladder conditions with well-established causes include:
- radiation cystitis
- cystitis caused by microorganisms that are not detected by
routine culture methodologies
- systemic disorders that affect the bladder
- gynecologic disorders
n Symptoms are mostly allodynic, an exaggeration of normal
n There are no pathognomonic findings on pathologic examination
n Petechial hemorrhages after hydrodistention is no longer
considered the sine qua non of PBS/IC
n PBS/IC is truly a diagnosis of exclusion. It may have multiple
causes and represent a final common reaction of the bladder to
different types of insults.
n IC was recognized as a pathologic entity during the 19th century
n Joseph Parrish, a Philadelphia surgeon, described three cases of severe lower urinary tract
symptoms in the absence of a bladder stone in an 1836 text and termed the disorder "tic
doloureux of the bladder."
n 1887 Skene used the term interstitial cystitis to describe an inflammation that has "destroyed the
mucous membrane partly or wholly and extended to the muscular parietes.“
n Early 20th century, Guy Hunner reported on eight women with a history of suprapubic pain,
frequency, nocturia, and urgency lasting an average of 17 years . They had red, bleeding
n 1949 Hand reported 223 cases "I have frequently observed that what appeared to be a normal
mucosa before and during the first bladder distention showed typical interstitial cystitis on
subsequent distention." He notes, "small, discrete, submucosal hemorrhages, showing variations
in form, and dot-like bleeding points”
n 1978 Walsh coined the term glomerulations to describe the petechial hemorrhages that Hand had
n 1978 Stamey discussed the "early diagnosis" of IC that attention turned from looking for an ulcer
to make the diagnosis to the concepts that (1) symptoms and glomerulations at the time of
bladder distention under anesthesia were the disease hallmarks and (2) the diagnosis was
primarily one of exclusion
n Dr. Vicki Ratner, an orthopedic surgery resident in New York City, who founded the first patient
advocacy group, the Interstitial Cystitis Association, in the living room of her New York City
apartment in 1984
n Interstitial cystitis (IC) - clinical diagnosis primarily based on symptoms of
urgency/frequency and pain in the bladder and/or pelvis.
- The International Continence Society (ICS) prefers the term painful
bladder syndrome (PBS), defined as "the complaint of suprapubic
pain related to bladder filling, accompanied by other symptoms such
as increased daytime and night-time frequency, in the absence of
proven urinary infection of other obvious pathology”
n The ICS reserves the diagnosis of IC for patients with "typical cystoscopic
and histological features," without further specifying these. In the absence of
clear criteria for "IC," this chapter will refer to PBS/IC and IC interchangeably
National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) Diagnostic Criteria for Interstitial Cystitis
n To be diagnosed with interstitial cystitis, patients must have either glomerulations or a classic Hunner ulcer, and
they must have either pain associated with the bladder or urinary urgency. An examination for glomerulations
should be undertaken after distention of the bladder under anesthesia to 80 to 100 cm H2O for 1 to 2 minutes.
The bladder may be distended up to two times before evaluation. The glomerulations must be diffuse-present in at
least three quadrants of the bladder-and there must be at least 10 glomerulations per quadrant.
n The presence of any one of the following excludes a diagnosis of interstitial cystitis:
n 1. Bladder capacity of greater than 350 mL on awake cystometry using either a gas or liquid filling medium
n 2. Absence of an intense urge to void with the bladder filled to 100 mL of gas or 150 mL of liquid filling medium
n 3. The demonstration of phasic involuntary bladder contractions on cystometry using the fill rate just described
n 4. Duration of symptoms less than 9 months
n 5. Absence of nocturia
n 6. Symptoms relieved by antimicrobial agents, urinary antiseptic agents, anticholinergic agents, or antispasmodics
n 7. A frequency of urination while awake of less than 8 times per day
n 8. A diagnosis of bacterial cystitis or prostatitis within a 3-month period
n 9. Bladder or ureteral calculi
n 10. Active genital herpes 15. Uterine, cervical, vaginal, or urethral cancer
n 11. Urethral diverticulum 16. Cyclophosphamide or any type of chemical cystitis
n 12. Tuberculous cystitis 17. Radiation cystitis
n 13. Benign or malignant bladder tumors 18. Vaginitis
n 14. Age younger than 18 years Roc suggested adding mom with IC
n Recent international consultations have essentially agreed that
the nomenclature of "interstitial cystitis" be revised to "painful
bladder syndrome/interstitial cystitis.“
n This recognizes that it is the symptoms that drive treatment,
and the question as to whether IC refers to a distinct
subgroup of the painful bladder syndrome is, as yet,
n For purposes of PBS/IC, the symptom of pain should be
broadened to include "pressure" and "discomfort."
Interstitial Cystitis Database (ICDB) Study
n 1. Providing informed consent to participate in the study.
n 2. Willing to undergo a cystoscopy under general or regional anesthesia when indicated, during the course of the study.
n 3. At least 18 years of age.
n 4. Having symptoms of urinary urgency, frequency, or pain for more than 6 months.
n 5. Urinating at least 7 times per day, or having some urgency or pain (measured on linear analog scales).
n 6. No history of current genitorurinary tuberculosis.
n 7. No history of urethral cancer.
n 8. No history of bladder malignancy, high-grade dysplasia, or carcinoma in situ
n 9. Males: no history of prostate cancer.
n 10. Females: no occurrence of ovarian, vaginal, or cervical cancer in the previous 3 years
n 11. Females: no current vaginitis, clue cell, trichomonas, or yeast infections.
n 12. No bacterial cystitis in the previous 3 months.
n 13. No active herpes in the previous 3 months.
n 14. No antimicrobials for urinary tract infections in previous 3 months.
n 15. Never having been treated with cyclophosphamide.
n 16. No radiation cystitis.
n 17. No neurogenic bladder dysfunction (e.g., due to a spinal cord injury, stroke, Parkinson's disease, multiple sclerosis,
spina bifida, or diabetic cystopathy).
n 18. No bladder outlet obstruction (determined by urodynamic investigation).
n 19. Males: no bacterial prostatitis for previous 6 months.
n 20. Absence of bladder, ureteral, or urethral calculi for previous 3 months.
n 21. No urethritis for previous 3 months.
n 22. Not having had a urethral dilation, cystometrogram, bladder cystoscopy under full anesthesia, or a bladder biopsy in
previous 3 months.
n 23. Never having had an augmentation cystoplasty, cystectomy, cystolysis, or neuroectomy.
n 24. Not having a urethral stricture of less than 12 French.
n Epidemiology studies are hampered by many problems.
- Lack of an accepted definition
- Absence of a validated diagnostic marker
- Questions regarding etiology and pathophysiology make much of the
literature difficult to interpret
- Most apparent when one looks at the variation in prevalence reports in
the United States 20,000 per 100,000 women vs. 1.2 per 100,000
population in Japan
n It has been estimated that the prevalence of
chronic pain due to benign causes in the
population is at least 10%
n A childhood presentation is extremely rare
and must be differentiated from the much
more common and benign-behaving
extraordinary urinary frequency syndrome of
n Held et al, 1990- Surveyed: (1) randomly 127 board-certified urologists, (2) 64 IC patients
selected by the surveyed urologists and divided between the last patient with IC seen and the last
patient with IC diagnosed, (3) 904 female patients belonging to the Interstitial Cystitis Association,
and (4) a random phone survey of 119 persons from the U.S. population. This study reached the
n 1. There were 43,500 to 90,000 diagnosed cases of IC in the United States (twice the Finnish
n 2. Up to a fivefold increase in IC prevalence occurred if all patients with painful bladder and sterile
urine had been given the diagnosis, yielding up to a half million possible cases in the United
n 3. Median age at onset is 40 years.
n 4. Late deterioration in symptoms is unusual.
n 5. There is a 50% temporary spontaneous remission rate, with a mean duration of 8 months.
n 6. The incidence of childhood bladder problems is 10 times higher in IC patients versus controls.
n 7. The incidence of a history of urinary tract infection is twice that of controls.
n 8. Fourteen percent of IC patients were Jewish versus 3% who were Jewish in a general
n 9. IC patients have a lower quality of life than dialysis patients.
n 10. Costs including lost economic production, in 1987, were $427 million.
n Prevalence estimates per 100,000 persons
n United States: 15-24,000
n Netherlands: 7
n Finland: 10.6-450
n Japan: 1.2
n Female to male ratio = 5:1
n No reports have ever documented a relationship to suggest
that IC is a premalignant lesion.
n Focal vulvitis/vulvar
n Sjögren's syndrome
n It is likely that PBS/IC has a multifactorial etiology that may act
predominantly through one or more pathways resulting in the typical
n feline urologic syndrome
n Diagnosis of PBS/IC is made only after a patient has been seen by a
number of physicians and treated with antibiotics for presumed urinary
tract infection without resolution of symptoms
n The symptom-complex looks to the patient and physician like an
n Not just urine but bladder epithelium as well must be cultured for
appropriate microorganisms, including bacteria, viruses, and fungi
n The role of infection in the pathogenesis of IC remains a mystery. At this
time there are little data to support the role of an infectious etiology but
investigators keep returning to an infectious theory.
n "It is logical to suggest that even if organisms are not causative
agents, their presence may lead to immune and host-cell
responses that could initiate or exacerbate an inflammatory state."
n Immune/neuroimmune mechanisms may have an important
role in the pathogenesis of PBS/IC.
-Excessive release of sensory nerve neurotransmitters and mast cell
inflammatory mediators is thought to be responsible for the development
and propagation of symptoms
n Can IC may represent some type of autoimmune disorder?
Three different possibilities exist:
(1) IC is caused by a direct autoimmune attack on the
(2) Some of the autoimmune symptoms and pathology
of IC arise indirectly as a result of tissue destruction
and inflammation from other causes
(3) Autoimmune phenomena in IC patients are
coincident and unrelated to the disease
n No clear indication of a primary role for autoimmunity as
the cause of IC has been observed
Mast Cell Involvement
n Mast cells have frequently been reported to be associated with
IC, both as a pathogenetic mechanism and as a pathognomonic
n Mast cells are strategically localized in the urinary bladder close
to blood vessels, lymphatics, nerves and detrusor smooth
n Studies strongly suggest that IC is a syndrome with neural,
immune, and endocrine components in which activated
mast cells play a central, although not primary, pathogenetic
role in many patients
Bladder GAG Layer/Epithelial
n Parsons hypothesized that IC is the result of some defect in the epithelial
permeability barrier of the bladder surface glycosaminoglycans
n Major classes of glycosaminoglycans (GAGs) include hyaluronic acid, heparin
sulfate, heparin, chondroitin 4-sulfate and chondroitin 6-sulfate, dermatan
sulfate, and keratan sulfate
n Does seems that there is a population of IC patients with increased epithelial
n Treatments that tend to damaged GAG layer, including transurethral
resection and laser of ulcerated areas, bladder
distention, silver nitrate administration, and
use of the organic solvent DMSO have all been
used with varying results to treat IC.
n Conclusion: Increased permeability and epithelial
dysfunction must be only a part of the story.
n Inflammatory painful stimuli, especially if repeated, can chronically alter
innervation, central pain-processing mechanisms, and tissue responses
n Numerous studies indicate increased sympathetic activity in IC
n Important to note that the nervous system itself almost surely contributes to the
chronic nature of this pain syndrome, regardless of initiating etiology
n Non-nociceptive Pain: Characteristic Clinical Features
n 1. The description of the pain seems inappropriate in comparison with the
degree of tissue pathology, or no tissue pathology may be discernible.
n 2. Noxious stimuli result in a pain experience that is greater and more
unpleasant than would normally be expected (hyperalgesia).
n 3. Normally non-noxious stimuli may result in pain (allodynia).
n 4. The extent of the pain boundary is greater than would be expected on the
basis of the site of the original tissue pathology.
n Antiproliferative Factor (APF) - The finding that cells from the bladder
lining of normal controls grow significantly more rapidly in culture than
cells from IC patients led to the discovery of an (APF) produced by the
urothelium of IC patients.
n It is 8 protein produced by bladder uroepithelial cells of PBS/IC patients.
n Inhibits bladder cell proliferation
n Is a sensitive and specific biomarker for IC.
n It may ultimately unlock the etiology of the syndrome and could provide
avenues for development of future therapies.
Other Potential Causes
n Pelvic floor dysfunction
n Obstruction of lymphatics or vascular structures
n One can have pathology consistent with the diagnosis of IC, but
there is no microscopic picture pathognomonic of this syndrome.
The role of histopathology in the diagnosis of IC is primarily one
of excluding other possible diagnoses
Nonulcerative form of interstitial cystitis with Knifelike Hunner's ulcer in interstitial cystitis.
dense lymphoid infiltrate in the lamina propria
n Considered one/part of the chronic visceral pain syndromes, affecting the
urogenital and rectal area, well described but poorly understood (Including
vulvodynia, orchialgia, penile pain, perineal pain, and rectal pain)
n Various gynecologic problems can mimic the pain of IC
n Laparoscopy should not be considered a part of any routine evaluation of
PBS/IC unless a gynecologist believes it is likely to benefit the patient.
n Presumptive diagnosis can be made merely by ruling out known causes of
frequency and pain/urgency in a patient with compatible chronic symptoms
(Complete H&P, cultures, and cystoscopy)
n Cystometry in conscious IC patients generally demonstrates normal function, the
exception being decreased bladder capacity and hypersensitivity.
n Pain on bladder filling that reproduces the
patient's symptoms is very suggestive of
Typical appearance of glomerulations after bladder Typical appearance of Hunner's ulcer in
distention in a patient with nonulcerative interstitial a patient with interstitial cystitis before
cystitis. bladder distention.
Potassium Chloride Test
n Parsons has championed an intravesical KCl challenge, comparing the sensory
nerve provocative ability of sodium versus potassium using a 0.4 M KCl solution.
Pain and provocation of symptoms constitutes a positive test.
n Whether the results indicate abnormal epithelial permeability in the subgroup of
positive patients or hyper-sensitivity of the sensory nerves is unclear
n IF used as a diagnostic test for IC, the KCl test is not valid
n Is very non-specific
n Recent study reported a 36% false-positive rate in asymptomatic men
n Prospective and retrospective studies looking at the KCl test for diagnosis in
patients presenting with symptoms of PBS/IC have found no benefit of the test in
comparison with standard techniques of diagnosis
n Is a predictive test for response to IC-specific medications (Elmiron and other
heparinoids that work by “coating” the bladder lining)
CLINICAL SYMPTOM SCALES
n There are three published PBS/IC symptom
1) University of Wisconsin IC Scale
2) O'Leary-Sant IC Symptom Index
3) Pelvic Pain and Urgency/Frequency
n Pelvic Pain and Urgency/Frequency Patient
Symptom Scale (PUF)
n Global Response Assessment (GRA)
n It has been not only a difficult condition to
diagnose but also a difficult condition for
which to assess therapeutic impact.
n In a chronic, devastating condition with
primarily subjective symptomatology, no
known cause, and no cure, patients are
desperate and often seem to respond to
any new therapy (at least short term)
n Placebo effects plus disease natural history
of regression can result in high rates of
good outcomes, which may be
misattributed to specific treatment effects
Percentage of patients initially improved
n Patient education and empowerment is an important initial step in therapy
n There are data that timed voiding and behavioral modification therapy can be
helpful in the short-term, especially in patients in whom frequency rather than
n Interstitial Cystitis Association Recommendations of Foods to Avoid:
n Milk/Dairy Products Nuts Aged cheeses Sour cream
n Alcoholic beverages Yogurt Carbonated drinks Chocolate
n Coffee Vegetables Tea Fruit juices
n Fava beans Lima beans Seasonings Onions
n Mayonnaise Tofu Ketchup Soybeans
n Mustard Tomatoes Salsa Fruits
n Spicy foods Soy sauce Apples Miso
n Apricots Salad dressing Avocados Vinegar
n Bananas Cantaloupes Preservatives and Additives Citrus
n Fruits Benzyl alcohol Cranberries Citric acid
n Grapes MSG Nectarines Artificial
n Peaches Pineapples Food coloring Pomegranates
n Rhubarb Strawberries Tobacco Caffeine
n Diet pills Junk foods Rye bread Recreational drugs
n Sourdough bread Allergy medications with ephedrine or pseudoephedrine
n Meats and Fish Certain vitamins Aged, canned, cured, processed, smoked meats
n Tricyclic Antidepressants (Amitriptyline) have three major pharmacologic
(1) central and peripheral anticholinergic actions
(2) block the active transport system in the presynaptic nerve ending
responsible for reuptake of serotonin and noradrenaline
(3) they are sedatives
n Antihistamines- Used since late 1950s, postulated that the local release of
histamine may be responsible for, or accompany the development of, IC.
n Sodium Pentosan Polysulfate- A heparin analog, thought to decrease the
epithelial permeability barrier (GAG layer)
- 3% to 6% of which is excreted into the urine from oral pill
n Systemic corticosteroids
n Vitamin E
n Calcium channel antagonist (nifedipine)
n Cysteinyl leukotriene D4 receptor antagonist
n Oral L-arginine, an over-the-counter amino
acid preparation, was purported to
increase nitric oxide-related enzymes
n The long-term, appropriate use of pain medications forms an integral
part of the treatment of a chronic pain condition such as IC
n With the results of major surgery anything but certain, the use of long-
term opioid therapy in the rare patient who has failed all forms of
conservative therapy over many years may also be considered
n Intravesical lavage with one of a variety of preparations has remained a
mainstay of treatment in the therapeutic armamentarium of IC
n Drug Randomized Controlled Trial % Success
Silver nitrate No 60%
Clorpactin WCS-90 No 60%
Dimethylsulfoxide Yes 70%
Bacillus Calmette-Guérin Yes No proven efficacy
n Resiniferatoxin Yes No proven efficacy
Hyaluronic acid Yes No proven efficacy
Heparin No 60%
Chondroitin sulfate No 33%
Lidocaine No 65%
Capsaicin No No demonstrated efficacy
Oxybutynin No Efficacy suggested
Doxorubicin No Anecdotal efficacy
Pentosan polysulfate Yes 40%
Dimethyl sulfoxide (DMSO)
n DMSO is a product of the wood pulp industry and a derivative of lignin
n It has exceptional solvent properties and is freely miscible with water, lipids, and
n Pharmacologic properties include membrane penetration, enhanced drug
absorption, anti-inflammatory action, analgesic action, collagen dissolution,
muscle relaxation, and mast cell histamine release
n It has been suggested that DMSO actually desensitizes nociceptive pathways in
the lower urinary tract
n Authors administer 50 mL of 50% DMSO as a bladder "cocktail" with 10 mg of
triamcinolone 40,000 units of heparin, and 44 mEq of sodium bicarbonate
n It is reasonable to consider therapeutic options that directly interface with the
nervous system in the treatment of PBS/IC. This approach is further supported
by the association of pelvic floor dysfunction with pelvic pain syndromes
n Direct sacral nerve stimulation has been explored in the treatment of IC
and urgency/frequency and is referred to as neuromodulation
n As initially practiced, trial stimulation was performed with a percutaneous
temporary electrode for a 3- to 4-day temporary stimulation period to access
n The S3 nerve is most frequently used
n A wire electrode is inserted into the foramen and connected to
an external pulse generator
n If the trial is successful, the patient would be considered
for implantation of a permanent neural prosthesis.
n More recently, a staged procedure has supplanted the
traditional percutaneous approach (or in a van down by the
n Hydrodistention of the bladder under anesthesia
n Technically a surgical treatment, is often the first therapeutic modality employed
n Often as a part of the diagnostic evaluation
n Results vary markedly
n Our method is to perform an initial cystoscopic examination (which is generally
unremarkable), obtain urine for cytology, and distend the bladder for 1 to 2
minutes at a pressure of 80 cm H2O. The bladder is emptied and then refilled to
look for glomerulations or ulceration. A therapeutic hydraulic distention follows
for another 8 minutes. Biopsy, if indicated, is performed after the second
n Responses in patients with a bladder capacity under anesthesia of less than 600
mL showed 26% with an excellent and 29% with
a fair result
n The surgical therapy of IC is an option after all trials of conservative
treatment have failed, a point that cannot be overemphasized
n IC, although a cause of significant morbidity, is a nonmalignant process with a
temporary spontaneous remission rate of up to 50% and does not directly result
n Many surgical approaches have been employed for IC:
n Sympathectomy and intraspinal alcohol injections
n Differential sacral neurotomy
n Transurethral resection/laser of a Hunner's ulcer
n Supratrigonal cystectomy
n Urinary diversion with or without cystourethrectomy is the ultimate
surgical answer to the dilemma of IC
PRINCIPLES OF MANAGEMENT
n History/Initial Assessment
The initial assessment consists of a frequency/volume chart, focused physical
examination, urinalysis, and urine culture. Cytology and cystoscopy are recommended if
clinically indicated. Only if findings are unable to explain the symptoms are they
diagnosed with PBS/IC.
n Initial Treatment
Patient education, dietary manipulation, nonprescription analgesics, and pelvic floor
relaxation techniques. When these fail, or symptoms are severe and conservative
management unlikely to succeed, oral medication or intravesical treatment can be
n Secondary Assessment
It is reasonable to consider further evaluation (urodynamics, pelvic imaging, and
cystoscopy with bladder distention and possible bladder biopsy under anesthesia).
PRINCIPLES OF MANAGEMENT
n Refractory PBS/IC
Pts. with persistent, unacceptable symptoms despite oral and/or intravesical therapy
are candidates for more aggressive modalities (neuromodulation, pain clinic consultation,
narcotic analgesia, and/or experimental protocols). The last step in treatment is usually
some type of surgical intervention aimed at increasing the functional capacity of the bladder
or diverting the urine stream (augmentation).
n A Philosophy of Management
I believe that, because of the natural history of the disorder, it is best to cautiously
progress through a variety of treatments. One should encourage patients to maximize their
activity and live as normal a life as possible, not becoming a prisoner of the condition.
Although some activities or foods may aggravate symptoms, nothing has been shown to
negatively affect the disease process itself. Therefore, patients should feel free to
experiment and judge for themselves how to modify their lifestyle without the guilt that
comes from feeling they have harmed themselves if symptoms flare.
n In 1945, the distinguished American physician Richard Cabot was quoted as
having stated that “any pain within two feet of the female urethra for which one
cannot find an adequate explanation should be suspected of coming from the
n The urethral syndrome is a very nonspecific constellation of symptoms including
urinary frequency, urgency, dysuria, and suprapubic discomfort without any
objective findings of urologic abnormality to account for the symptoms
n The concept of the urethral syndrome, chronic or acute, is now essentially
a historical one and no longer alluded to in the modern medical literature