1. health and fitness
2. disease

10
Painful Bladder
Syndrome/Interstitial
Cystitis and Related
Disorders
HISTORICAL PERSPECTIVE
DEFINITION
EPIDEMIOLOGY
Associated disorders
ETIOLOGY
Animal models
Infection
Autoimmunity / inflammation
Mast cell involvement
Bladder glycosaminoglycan layer and epithelial
permeability
Neurobiology
Urine abnormalities
Antiproliferative factor
Other potential etiologies
PATHOLOGY
INTRODUCTION
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INTRODUCTION
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PHILIP M. HANNO, MD
DIAGNOSIS
Markers
Potassium chloride test
CLINICAL SYMPTOM SCALES
ASSESSING TREATMENT RESULTS
CONSERVATIVE THERAPY
ORAL THERAPY
INTRAVESICAL THERAPY
NEUROMODULATION
HYDRODISTENTION
SURGICAL THERAPY
PRINCIPLES OF MANAGEMENT
Painful bladder syndrome / interstitial cystitis (PBS/IC) is a
condition diagnosed on a clinical basis and requiring a high
index of suspicion on the part of the clinician. Simply put, it
should be considered in the differential diagnosis of the
patient presenting with chronic pelvic pain, often exacerbated
by bladder filling, and associated with urinary frequency. The
perception that the original term, interstitial cystitis, was not
at all descriptive of the clinical syndrome or even the pathological findings in many cases, has led to the current effort to
reconsider the name of the disorder and even the way it is
positioned in the medical spectrum (Hanno 2005). What was
originally considered a bladder disease is now considered a
chronic pain syndrome (Janicki 2003) that may begin as a
pathologic process in the bladder in most but not all patients,
and eventually can develop into a disease in a small subset of
those affected that even cystectomy may not benefit (Hanno et
al. 2005). Its relationship to other chronic pelvic pain syndromes including the chronic pelvic pain syndrome in men
(previously referred to as nonbacterial prostatitis) is unclear
(Chai 2002; Hakenberg & Wirth 2002).
PBS/IC encompasses a major portion of the “painful bladder” disease complex, which includes a large group of patients
with bladder and/or urethral and/or pelvic pain, irritative
voiding symptoms (urgency, frequency, nocturia, dysuria),
and sterile urine cultures. Painful bladder conditions with
well-established etiologies include radiation cystitis, cystitis
caused by microorganisms that are not detected by routine
culture methodologies, and systemic disorders that affect the
bladder. In addition, many gynecologic disorders can mimic
PBS/IC (Kohli, Sze, & Karram 1997; Howard 2003a; Howard
2003b).
The symptoms are mostly allodynic, an exaggeration of
normal sensations. Urinary frequency patterns can be related
to fluid intake and age, and the signal or urge to void is considered an unpleasant or painful sensation by most persons
(Burgio, Engel, & Locher 1991). There are no pathognomonic
findings on pathologic examination, and even the finding of
petechial hemorrhages on the bladder mucosa during cystoscopy after bladder hydrodistention under anesthesia is no
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Physiology, Pathology, and Management of Upper Urinary Tract Diseases
HISTORICAL PERSPECTIVE
Recent historical reviews confirm that interstitial cystitis was
recognized as a pathologic entity during the 19th century
(Christmas 1997; Parsons & Parsons 2004). Joseph Parrish, a
Philadelphia surgeon, described 3 cases of severe lower urinary tract symptoms in the absence of a bladder stone in an
1836 text (Parrish 1836), and termed the disorder “tic
doloureux of the bladder”. Teichman argues that this may represent the first description of interstitial cystitis (Teichman,
Thompson, & Taichman 2000). Fifty years later 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” (Skene 1887).
Early in the 20th century, at a New England Section meeting of the American Urological Association, Guy Hunner
reported on 8 women with a history of suprapubic pain, frequency, nocturia, and urgency lasting an average of 17 years
(Hunner 1915; Hunner 1918). He drew attention to the disease, and the red, bleeding areas he described on the bladder
wall came to have the pseudonym “Hunner’s ulcer”. As Walsh
(Walsh 1978) observed, this has proven to be unfortunate. In
the early part of the 20th century, the very best cystoscopes
available gave a poorly defined and ill-lit view of the fundus of
the bladder. It is not surprising that when Hunner saw red and
bleeding areas high on the bladder wall, he thought they were
ulcers. For the next 60 years, urologists would look for ulcers
and fail to make the diagnosis in their absence. The disease
was thought to be a focal, rather than a pancystitis.
Hand (Hand 1949) authored the first comprehensive
review about the disease, reporting 223 cases. In looking back,
his paper was truly a seminal one, years ahead of its time.
Many of his epidemiologic findings have held up to this day.
His description of the clinical findings bears repeating. “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…dot-like bleeding points…little or no restriction to
bladder capacity.” He portrays three grades of disease, with
grade 3 matching the small-capacity, scarred bladder
described by Hunner. Sixty-nine percent of patients were
grade 1 and only 13% were grade 3.
Walsh (Walsh 1978)later coined the term “glomerulations”
to describe the petechial hemorrhages that Hand had
described. But it was not until Messing and Stamey (Messing
& Stamey 1978) 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.
Although memorable and right on the mark, this description and others like it were not suitable for defining this disease in a manner that would help physicians make the diagnosis and design research studies to learn more about the
problem. Physician interest and government participation in
research were sparked through the efforts of a group of frustrated patients led by 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 (Ratner, Slade,
& Whitmore 1992; Ratner & Slade 1997). The first step was to
develop a working definition of the disease. The modern history of PBS/IC is best viewed through the perspective of definition.
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longer considered the sine qua non of PBS/IC that it had been
until a decade ago (Waxman, Sulak, & Kuehl 1998). 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 insult.
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KEY POINTS
Bourque’s Aunt Minnie (she is hard to define, but you
know her when you see her) description of IC is over
50 years old and is worth recalling. “We have all met,
at one time or another, patients who suffer chronically
from their bladder; and we mean the ones who are
distressed, not only periodically but constantly, having
to urinate often, at all moments of the day and of the
night, and suffering pains every time they void. We all
know how these miserable patients are unhappy, and
how those distressing bladder symptoms get finally to
influence their general state of health physically at
first, and mentally after a while.” (Bourque 1951)
DEFINITION
Interstitial cystitis (IC) is a 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 or other obvious pathology” (Abrams et al. 2002).
ICS reserves the diagnosis IC to 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, as all but recent literature terms the syndrome “IC”. Perhaps more than for most
diseases, how we arrived at this point is instructive and critical to an overall understanding of PBS/IC.
“….It resembles a constellation of stars; its components are
real enough but the pattern is in the eye of the beholder”
(Makela & Heliovaara 1991). This evocative description of
fibromyalgia could equally apply to PBS/IC. Indeed, it has
been argued, not necessarily convincingly, that each medical
specialty has at least one somatic syndrome (irritable bowel
syndrome, chronic pelvic pain, fibromyalgia, tension
headache, noncardiac chest pain, hyperventilation syndrome)
that might be better conceptualized as a part of a general functional somatic syndrome than with the symptom-based classification that we have now that may be more a reflection of
professional specialization and access to care (Wessely &
White 2004).
There are data to suggest that true urinary frequency in
women can be defined as regularly having to void at intervals
of less than 3 hours, and that of women older than 40 years,
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sion criteria 4, 5, 6, 8, 9, 11, 12, 17, and 18 are only relative.
What percentage of patients with idiopathic “sensory
urgency” has IC is unclear (Frazer, Haylen, & Sissons 1990).
The specificity of the finding of bladder glomerulations has
come into question (Erickson 1995; Waxman, Sulak, & Kuehl
1998; Tomaszewski et al. 2001). Similarly, the sensitivity of
glomerulations is also unknown, but clearly patients with IC
symptoms can demonstrate an absence of glomerulations
under anesthesia (Awad et al. 1992; Al Hadithi et al. 2002).
Bladder ulceration is extremely rare and accounts for less than
5% of patients in this author’s experience and in the experience of others (Sant 1991). A California series found 20% of
patients to have ulceration (Koziol 1994). Specific pathologic
findings represent a glaring omission from the criteria,
because there is a lack of consensus as to which pathologic
findings, if any, are required for, or even suggestive of, a tissue
diagnosis (Hanno et al. 1990; Tomaszewski et al. 1999;
Tomaszewski, Landis, Russack, Williams, Wang, Hardy,
Brensinger, Matthews, Abele, Kusek, & Nyberg 2001; Hanno,
Baranowski, Fall, Gajewski, Nordling, Nyberg, Ratner,
Rosamilia, & Ueda 2005; Hanno 2005;).
The unexpected use of the NIDDK research criteria by the
medical community as a definition of IC led to concerns that
many patients suffering from this syndrome might be misdiagnosed. The multicenter Interstitial Cystitis Database
(ICDB) study through NIDDK accumulated data on 424
patients with IC, enrolling patients from May 1993 through
December 1995. Entry criteria were much more symptomdriven than those promulgated for research studies (Simon et
al. 1997) and are noted in Table 10-2. In an analysis of the
defining criteria (Hanno et al. 1999b; Hanno et al. 1999a), it
appeared the NIDDK research criteria fulfilled their mission.
Fully 90% of expert clinicians agreed that patients diagnosed
with IC by those criteria in the ICDB indeed had the disorder.
However, 60% of patients deemed to have IC by these experi-
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25% have nocturia at least once (Glenning 1985; Fitzgerald &
Brubaker 2003). Whereas bladder capacity tends to fall in
women by the eighth and ninth decades of life, bladder volume at first desire to void tends to rise as women age (Collas
& Malone-Lee 1996). Based on a 90th percentile cut-off to
determine the ranges of normality, the highest normal frequency varies in the 4th decade range from 6 for men to 9 for
women (Burgio, Engel, & Locher 1991). Large variation in the
degree of bother with varying rates of frequency (Fitzgerald et
al. 2002) makes a symptomatic diagnosis of PBS/IC based on
an absolute number of voids subject to question, and frequency per volume of intake or even the concept of “perception of frequency” as a problem may be more accurate than an
absolute number.
In an effort to define IC so that patients in different geographic areas, under the care of different physicians, could be
compared, the National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK) held a workshop in August
1987 at which consensus criteria were established for the diagnosis of IC (Gillenwater & Wein 1988). These criteria were not
meant to define the disease, but rather to ensure that groups
of patients included in basic and clinical research studies
would be relatively comparable. After pilot studies testing the
criteria were carried out, the criteria were revised at another
NIDDK workshop a year later (Wein, Hanno, & Gillenwater
1990). These criteria are presented in Table 10-1.
Although meant initially to serve only as a research tool, the
NIDDK “research definition” became a de facto definition of
this disease, diagnosed by exclusion and colorfully termed a
“hole in the air” by Hald (George 1986). Certain of the exclusion criteria serve mainly to make one wary of a diagnosis of
IC, but should by no means be used for categorical exclusion
of such a diagnosis. However, because of the ambiguity
involved, these patients should probably be eliminated from
research studies or categorized separately. In particular, exclu-
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Table 10–1. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diagnostic Criteria
for Interstitial Cystitis
To be diagnosed with interstitial cystitis, patients must have either glomerulations on cystoscopic examination or a classic Hu
Hunner’s 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 80-100 cm of water pressure 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 3 quadrants of the bladder –and there must be at least 10 glomerulations per quadrant. The
glomerulations must not be along the path of the cystoscope (to eliminate artifact from contact instrumentation). The presence of any one of the following excludes a diagnosis of interstitial cystitis:
1. Bladder capacity of greater than 350cc on awake cystometry using either a gas or liquid filling medium.
2. Absence of an intense urge to void with the bladder filled to 100 cc of gas or 150 cc of liquid filling medium.
3. The demonstration of phasic involuntary bladder contractions on cystometry using the fill rate described above.
4. Duration of symptoms less than 9 months.
5. Absence of nocturia.
6. Symptoms relieved by antimicrobials, urinary antiseptics, anticholinergics, or antispasmodics.
7. A frequency of urination while awake of less than 8 times per day.
8. A diagnosis of bacterial cystitis or prostatitis within a 3 month period.
9. Bladder or ureteral calculi.
10. Active genital herpes.
11. Uterine, cervical, vaginal, or urethral cancer.
12. Urethral diverticulum
13. Cyclophosphamide or any type of chemical cystitis.
14. Tuberculous cystitis.
15. Radiation cystitis.
16. Benign or malignant bladder tumors.
17. Vaginitis.
18. Age less than 18 years.
From Wein, AJ, Hanno, PM, et.al: Interstitial cystitis: An introduction to the problem. In Hanno, PM, Staskin, DR, Krane, RJ, Wein, AJ (eds): Interstitial
Cystitis. London, Springer-Verlag, 1990, pp13-15.
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Table 10–2.
18.
19.
20.
21.
22.
23.
24.
Providing informed consent to participate in the study.
Willing to undergo a cystoscopy under general or regional anesthesia when indicated, during the course of the study.
At least 18 years of age.
Having symptoms of urinary urgency, frequency, or pain for more than 6 months.
Urinating at least 7 times per day, or having some urgency or pain (measured on linear analog scales).
No history or current genitor-urinary tuberculosis.
No history of urethral cancer.
No history of bladder malignancy, high-grade dysplasia, or carcinoma in situ.
Males: no history of prostate cancer.
Females: no occurrence of ovarian, vaginal, or cervical cancer in the previous 3 years.
Females: no current vaginitis, clue cell, trichomonas, or yeast infections.
No bacterial cystitis in the previous 3 months.
No active herpes in the previous 3 months.
No antimicrobials for urinary tract infections in previous 3 months.
Never having been treated with cyclophosphamide.
No radiation cystitis.
No neurogenic bladder dysfunction (e.g., due to a spinal cord injury, stroke, Parkinson’s disease, multiple sclerosis, spina bifida, or diabetic cystopa
thy).
No bladder outlet obstruction (determined by urodynamic investigation).
Males: no bacterial prostatitis for previous 6 months.
Absence of bladder, ureteral, or urethral calculi for previous 3 months.
No urethritis for previous 3 months.
Not having had a urethral dilation, cystometrogram, bladder cystoscopy under full anesthesia, or a bladder biopsy in previou
previous 3 months.
Never having had an augmentation cystoplasty, cystectomy, cystolysis, or neuroectomy.
Not having a urethral stricture of less than 12 French.
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1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Interstitial Cystitis Database (ICDB) Study Eligibility Criteria
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From Simon LJ, Landis JR, et al: The Interstitial Cystitis Data Base Study: Concepts and preliminary baseline descriptive statistics. Urology 1997;49(5A):
64-75.
enced clinicians would not have met NIDDK research criteria.
Thus, IC remains a clinical syndrome defined by some combination of chronic symptoms of urgency, frequency, and/or
pain in the absence of other reasonable causation. Whereas IC
symptom and problem indices have been developed and validated (O'leary et al. 1997; Goin et al. 1998;), these are not
intended to diagnose or define IC but rather to measure the
severity of symptomatology and monitor disease progression
or regression (Moldwin & Kushner 2004).
Recent international consultations have essentially agreed
that the nomenclature of “interstitial cystitis” be revised to
“painful bladder syndrome / interstitial cystitis”. This recognizes that it is the symptoms that drive treatment, and the
question as to whether interstitial
interstitial cystitis refers to a distinct
subgroup of the painful bladder syndrome is, as yet, unclear.
The International Continence Society (ICS) definition of
painful bladder syndrome (Abrams, Cardozo, Fall, Griffiths,
Rosier, Ulmsten, Van Kerrebroeck, & Wein 2002) (suprapubic
pain related to bladder filling, accompanied by other symptoms such as increased daytime and nighttime frequency in
the absence of infection or other pathology) appears to be a
useful one, highlighting, as it does, that pain is the primary
component of PBS/IC. For purposes of PBS/IC, the symptom
of pain should be broadened to include “pressure” and “discomfort”. Interstitial cystitis may be a subgroup that encompasses those patients with typical histological and cystoscopic
features (Peeker & Fall 2002), but what these features are is
still controversial and somewhat vague.
Urgency is a common complaint of this group of patients.
The ICS definition of urgency (Abrams, Cardozo, Fall,
Griffiths, Rosier, Ulmsten, Van Kerrebroeck, & Wein 2002),
“the complaint of a sudden compelling desire to pass urine,
which is difficult to defer”, could be interpreted as compatible
with either detrusor overactivity or PBS/IC. Pain and pressure
are more involved in the frequency of PBS/IC and fear of
incontinence seems the reason for the urgency of overactive
bladder (Abrams, Hanno, & Wein 2005). Thus urgency is left
out of the definition of PBS/IC, as it would tend to obfuscate
the borders of overactive bladder and PBS/IC, and is unnecessary for definition purposes. Figure 10-1(Abrams, Hanno, &
Wein 2005) is a graphic depiction of one view of the relationship between these two, sometimes confused, conditions. The
14% incidence of urodynamic detrusor overactivity in the
PBS/IC patients (Nigro et al. 1997) is probably close to what
one might expect in the general population if studied urodynamically (Salavatore et al. 2003).
EPIDEMIOLOGY
Epidemiology studies of PBS/IC are hampered by many problems (Bernardini et al. 1999). The lack of an accepted definition, the absence of a validated diagnostic marker, and questions regarding etiology and pathophysiology make much of
the literature difficult to interpret. This is most apparent when
one looks at the variation in prevalence reports in the United
States and around the world. These range from 1.2 per
100,000 population and 4.5 per 100,00 females in Japan (Ito,
Miki, & Yamada 2000), to a questionnaire based study that
suggests a figure in American women of 20,000 per
100,000(Parsons & Tatsis 2004)!
It has been estimated that the prevalence of chronic pain
due to benign causes in the population is at least 10%
(Verhaak et al. 1998). Numerous case series have, until recently, formed the basis of epidemiologic information regarding
PBS/IC. Farkas and associates (Farkas, Waisman, & Goodwin
1977) discussed IC in adolescent girls. Hanash and Pool
(Hanash & Pool 1969) reviewed their experience with IC in
men. Geist and Antolak (Geist & Antolak, Jr. 1970) reviewed
and added to reports of disease occurring in childhood. A
childhood presentation is extremely rare and must be differentiated from the much more common and benign-behaving
extraordinary urinary frequency syndrome of childhood, a
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classic symptom complex occurred over a relatively short
time. IC does not progress continuously, but usually reaches
its final stage rapidly (within 5 years in the Koziol study
(Koziol, Clark, Gittes, & Tan 1993) and then continues without significant change in symptomatology. Subsequent major
deterioration was found by Oravisto to be unusual. The duration of symptoms before diagnosis was 3-5 years in the
Finnish study. Analogous figures in a classic American paper a
quarter of a century earlier were 7-12 years (Hand 1949).
Another early population study, this in the United States,
first demonstrated the potential extent of what had been
considered a very rare disease (Held, Hanno, & Wein 1990).
The following population groups were surveyed: 1)random
survey of 127 board-certified urologists 2)64 IC patients
selected by the surveyed urologists and divided among the last
patient with IC seen, and the last patient with IC diagnosed 3)
904 female patients belonging to the Interstitial Cystitis
Association 4) random phone survey of 119 persons from the
US population. This 1987 study reached the following conclusions:
1. 43,500 to 90,000 diagnosed cases of IC in the USA
(twice the Finnish prevalence)
2. Up to a five-fold increase in IC prevalence if all patients
with painful bladder, sterile urine had been given the
diagnosis, yielding up to half million possible cases in
the USA
3. Median age of onset 40 years
4. Late deterioration in symptoms unusual
5. 50% temporary spontaneous remission rate, mean
duration 8 months
6. 10 times higher incidence of childhood bladder problems in IC patients vs controls
7. 2 times the incidence of a history of urinary tract infection vs. controls
8. 14% of IC patients Jewish (15% in Koziol sample
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self-limited condition of unknown etiology (Koff & Byard
1988; Robson & Leung 1993). Nevertheless, there is a small
cohort of children with chronic symptoms of bladder pain,
urinary frequency, and sensory urgency in the absence of
infection who have been evaluated with urodynamics, cystoscopy, and bladder distention and have findings consistent
with the diagnosis of PBS/IC. In Close and colleague’s review
of 20 such children (Close et al. 1996), the median age of onset
was younger than 5 years, and the vast majority of patients
had long-term remissions with bladder distention.
A study conducted at the Scripps Research Institute (Koziol
et al. 1993) included 374 patients at Scripps as well as some
members of the Interstitial Cystitis Association, the large
patient support organization. A more recent, but similar study
in England (Tincello & Walker 2005) concurred with the
Scripps findings of urgency, frequency, and pain in the vast
majority of these patients, devastating effects on quality of
life, and often unsuccessful attempts at therapy with a variety
of treatments. Although such reviews provide some information, they would seem to be necessarily biased by virtue of
their design.
Several population-based studies have been reported in the
literature, and these studies tend to support the reviews of
selected patients or from individual clinics and the comprehensive follow-up case-control study by Koziol (Koziol 1994).
The first population-based study (Oravisto 1975) included
“almost all the patients with interstitial cystitis in the city of
Helsinki”. This superb, brief report from Finland surveyed all
diagnosed cases in a population approaching 1 million. The
prevalence of the disease in women was 18.1 per 100,000. The
joint prevalence in both sexes was 10.6 cases per 100,000. The
annual incidence of new female cases was 1.2 per 100,000.
Severe cases accounted for about 10% of the total. Ten per
cent of cases were in men. The disease onset was generally
subacute rather than insidious, and full development of the
5
OVERATIVE BLADDER (OAB) AND ITS RELATIONSHIP TO
PAINFUL BLADDER SYNDROME (PBS)
Urgency,
urgency
incontinence
Urgency
Frequency,
nocturia
Bladder
pain
PBS
OAB
14% incidence
of urodynamic
detrusor
overactivity in
IC patients
Figure 10–1. Relationship of overactive bladder to painful bladder syndrome: (From Abrams PH, Hanno PM, Wein AJ: Overactive bladder and painful bladder syndrome: there need not be confusion, Neurourol Urodyn, 24:149-150, 2005.)
CHAPTER 10
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patients has been carefully studied, and the findings seem to
bear out those of other epidemiologic surveys (Propert et al.
2000). Patterns of change in symptoms with time suggest
regression to the mean and an intervention effect associated
with the increased follow-up and care of cohort participants.
Although all symptoms fluctuated, there was no evidence of
significant long-term change in overall disease severity. The
data suggest that PBS/IC is a chronic disease and no current
treatments have a significant impact on symptoms over time
in the majority of patients. Quality of life studies suggest that
PBS/IC patients are 6 times more likely than individuals in the
general population to cut down on work time owing to health
problems, but only half as likely to do so as patients with
arthritis (Shea-O'Malley & Sant 1999). There is an associated
high incidence of comorbidity including depression, chronic
pain, and anxiety and overall mental health (Michael et al.
2000; Rothrock et al. 2002; Hanno, Baranowski, Fall, Gajewski,
Nordling, Nyberg, Ratner, Rosamilia, & Ueda 2005). There
seems to be no effect on pregnancy outcomes (Onwude &
Selo-Ojeme 2003).
Most studies show a female to male preponderance of 5:1 or
greater (Clemens et al. 2005; Hanno, Baranowski, Fall,
Gajewski, Nordling, Nyberg, Ratner, Rosamilia, & Ueda 2005).
In the absence of a validated marker, it is often difficult to distinguish PBS/IC from the chronic pelvic pain syndrome (nonbacterial prostatitis, prostatodynia) that affects males (Forrest
& Schmidt 2004), and the percentage of men with PBS/IC
may actually be higher (Miller et al. 1995; Miller, Bavendam,
& Berger 1997; Novicki, Larson, & Swanson 1998). Men tend
to be diagnosed at an older age and have a higher percentage
of Hunner’s Ulcer in the case series reported (Novicki, Larson,
& Swanson 1998; Roberts, Bergstralh, Bass, Lightner, Lieber, &
Jacobsen 2003).
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(Koziol 1994) vs 3% Jewish in general population
sample
9. Lower quality of life than dialysis patients
10. Costs including lost economic production in 1987 of
$427 million
Other population studies followed. Jones et al (Jones &
Nyberg 1997) obtained their data from self-report of a previous diagnosis of IC in the 1989 National Household Interview
Survey. The survey estimated that 0.5% of the population, or
>1,000,000 people in the United States reported having a
diagnosis of IC. There was no verification of this self-report
by medical records. Bade et al (Bade, Rijcken, & Mensink
1995) did a physician questionnaire-based survey in the
Netherlands yielding an overall prevalence of 8-16 per
100,000 females, with diagnosis heavily dependent on pathology and presence of mast cells. This prevalence in females
compares to 4.5 per 100,00 in Japan (Ito, Miki, & Yamada
2000). The Nurses Health Study I and II (Curhan et al. 1999)
showed a prevalence of IC between 52 and 67 per 100,000 in
the USA, twice the prevalence in the Held study (Held,
Hanno, & Wein 1990) and three-fold greater than the
Netherlands (Bade, Rijcken, & Mensink 1995). It improved on
previous studies by using a large sample derived from a general population and careful ascertainment of the diagnosis. If
the 6.4% confirmation rate of their study were applied to the
Jones et al National Health Interview Survey data, the prevalence estimates of the two studies would be nearly identical.
Leppilahti et al (Miller, Bavendam, & Berger 1997;
Leppilahti et al. 2002) used the O’Leary-Sant interstitial cystitis symptom and problem index (never validated for making a
diagnosis per se) to select persons with IC symptoms from the
Finnish population register. They calculated an incidence,
based on an index score of 12 or greater, of 450/100,000.
Roberts (Roberts et al. 2003), using a physician diagnosis as
the arbiter of IC, found annual incidence in Olmsted County,
Minnesota of 1.6 per 100,000 in women and 0.6 per 100,000
in men, a figure remarkably similar to that of Oravisto in
Helsinki. The cumulative prevalence by age >80 years in the
Minnesota study was 114 per 100,000, a figure comparable to
that in the Nurses Health Study if one takes into account the
younger age group in the Curhan data. Clemens calculated a
prevalence of diagnosed disease in a managed care population
of 197 per 100,000 women and 41 per 100,000 men, but when
the diagnosis was tested by eliminating those who had not
been evaluated with endoscopy or in whom exclusionary conditions existed, the numbers dropped considerably.
Whether the considerable variability in prevalence in studies within the United States and around the world is related to
methodology or true differences in incidence is an important
question yet to be answered. Familial occurrence of PBS/IC
has been reported (Dimitrakov 2001). A hereditary aspect to
incidence has been suggested by Warren in a pioneering study.
He found that adult female first-degree relatives of patients
with IC may have a prevalence of IC 17 times that found in the
general population. This, together with previously reported
evidence showing a greater concordance of IC among
monozygotic than dizygotic twins suggests, but does not
prove, a genetic susceptibility to IC that could partially explain
the discord in prevalence rates in different populations
(Warren et al. 2001; Warren et al. 2004).
The Interstitial Cystitis Database Cohort (ICDB) of
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KEY POINTS
Prevalence estimates per 100,000 persons (see text for
details):
■ USA: 35 – 24,000
■ Netherlands: 7
■ Finland: 10.6 -- 450
■ Japan: 1.2
■ Female : Male = 5:1
Associated Diseases
Knowledge of associated diseases is relevant for the clues it
engenders with regard to etiology and possible treatment of
this enigmatic pain syndrome. In a case-control study
Erickson found that patients with interstitial cystitis had higher scores than controls for pelvic discomfort, backache, dizziness, chest pain, aches in joints, abdominal cramps, nausea,
palpitations, and headache (Erickson et al. 2001). Buffington
theorizes that a common stress response pattern of increased
sympathetic nervous system function in the absence of comparable activation of the hypothalamic-pituitary-adrenal axis
may account for some of these related symptoms (Buffington
AL
is associated with a higher risk of bladder cancer, or transitions to cancer over time (Murphy, Zincke, & Utz 1982).
A large-scale survey of 6,783 individuals diagnosed by their
physicians as having IC studied the incidence of associated
disease in this population (Alagiri et al. 1997) (Fig 10-2). Data
from the 2405 responders was validated by comparison with
277 nonresponders. Allergies were the most common association with over 40% affected. Allergy was also the primary
association in Hand's study (Hand 1949). Thirty per cent of
patients had a diagnosis of irritable bowel syndrome, a finding confirming that of Koziol (Koziol 1994). Altered visceral
sensation has been implicated in irritable bowel syndrome in
that these patients experience intestinal pain at intestinal-gas
volumes that are lower than those that cause pain in healthy
persons (Lynn & Friedman 1993), strikingly similar to the
pain on bladder distention in IC.
Fibromyalgia, another disorder frequently considered functional because no specific structural or biochemical cause has
been found, is also overrepresented in the IC population. This
is a painful, non-articular condition predominantly involving
muscles; it is the commonest cause of chronic, widespread
musculoskeletal pain. It is typically associated with persistent
fatigue, nonrefreshing sleep and generalized stiffness. As in IC,
women are affected at least 10 times more often than men
(Consensus document 1993). The association is intriguing as
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2004). It has recently been hypothesized that panic disorder
may sometimes be a part of a familial syndrome that includes
interstitial cystitis, thyroid disorders, and other disorders of
possible autonomic or neuromuscular control (Weissman et
al. 2004).
Newly diagnosed patients are most concerned with the possibility that PBS/IC could be a forerunner of bladder carcinoma. No reports have ever documented a relationship to suggest that IC is a premalignant lesion. Utz and Zincke discovered bladder cancer in 12 of 53 men treated for IC at the Mayo
Clinic (Utz & Zincke 1973). Three of 224 women were eventually diagnosed with bladder cancer. Four years later additional cases were reported (Lamm & Gittes 1977). Tissot
(Tissot, Diokno, & Peters 2004) reported 1% of 600 patients
previously diagnosed as having IC were found to have transitional cell carcinoma as the cause of symptoms. Somewhat
ominously, 2 of these patients had no hematuria. In all
patients, irritative symptoms resolved after treatment of the
malignancy. From these experiences has come the dictum that
all patients with presumed IC should undergo cystoscopy,
urine cytology, and bladder biopsy of any suspicious lesion to
be sure that a bladder carcinoma is not masquerading as
PBS/IC. It would seem that in the absence of microhematuria,
and with a negative cytology, the risk of missing a cancer is
negligible, but not zero. There is no evidence that PBS/IC itself
7
Figure 10–2. Comparison of disease prevalence rates between the Interstitial Cystitis Association (ICA) study group patients who report symptoms of a disorder, who have been diagnosed with a disorder, and the general population. SLE, systemic lupus erythematosis. (From Alagiri M, Chottiner S et.al: Interstitial
cystitis: Unexplained associations with other chronic pain syndromes. Urology, 49 (Suppl 5A):52-57, 1997, with permission from Elsevier Science)
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
Inflammatory bowel disease was found in over 7% of the IC
population Alagiri studied, a figure 100 times higher than in
the general population. While unexplained at this time,
abnormal leukocyte activity has been implicated in both conditions (Bhone et al. 1962; Kontras et al. 1971).
Another mysterious disorder that has been associated with
interstitial cystitis is focal vulvitis. Vulvar vestibulitis syndrome is a constellation of symptoms and findings involving
and limited to the vulvar vestibule consisting of 1) severe pain
on vestibular touch to attempted vaginal entry, 2) tenderness
to pressure localized within the vulvar vestibule, and 3) physical findings confined to vulvar erythema of various degrees
(Marinoff & Turner 1991). McCormack (McCormack 1990)
reported on 36 patients with focal vulvitis 11 of whom also
had interstitial cystitis. Fitzpatrick (Fitzpatrick et al. 1993) has
added 3 more cases. The concordance of these noninfectious
inflammatory syndromes involving the tissues derived from
the embryonic urogenital sinus and the similarity of the
demographics argue for a common etiology.
An association has been reported between interstitial cystitis and Sjögren's syndrome (SS), an autoimmune exocrinopathy with a female preponderance manifested by dry eyes, dry
mouth, and arthritis, but which can also include fever, dryness, gastrointestinal and lung problems. Van De Merwe (Van
de et al. 1993), investigated 10 IC patients for the presence of
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both conditions have nearly identical demographic features,
modulating factors, associated symptoms, and response to tricyclic compounds (Clauw et al. 1997).
Vulvodynia, migraine headaches, endometriosis, chronic
fatigue syndrome, incontinence and asthma had similar
prevalence as in the general population. Several publications
have noted an association between IC and systemic lupus erythematosis (SLE) (Fister 1938; Boye et al. 1979; de la Serna &
Alarcon-Segovia 1981; Weisman, McDanald, & Wilson 1981;
Meulders et al. 1992). The question has always been as to
whether the bladder symptoms represent an association of
these two disease processes, or rather are a manifestation of
lupus involvement of the bladder or even a myelopathy with
involvement of the sacral cord in a small group of these
patients (Sakakibara et al. 2003). The beneficial response of
the cystitis of SLE to steroids (Meulders, Michel, Marteau,
Grange, Mougenot, Ronco, & Mignon 1992) tends to support
the latter view. No association with discoid lupus has been
demonstrated (Jokinen et al. 1972). While the actual numbers
are small, the Alagiri study demonstrated a 30-50 times
greater incidence of SLE in the IC group compared with the
general population. Overall, the incidence of collagen-vascular disease in the IC population is low. Parsons found only 2 of
225 consecutive IC patients to have a history of autoimmune
disorder (Parsons 1990).
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Bacterial
cystitis??
Primary
neurogenic
inflammation??
Bladder
trauma??
Autoimmune
disorder??
BLADDER
INSULT
Pelvic floor
dysfunction??
Bladder
overdistention??
Damage to bladder
epithelium
Antiproliferative
Bladder
factor secreted
fails to
by epithelial
repair
cells
damage
Lead of urine
constituents
(potassium) into
interstitum
C-fiber activation;
substance P
release
Mast cell
activation and
histamine release
Progressive
bladder injury
Figure 10–3. Hypothesis for etiologic cascade
of painful bladder syndrome/interstitial cystitis.
Immunogenic and
allergic responses
spinal cord changes
Possibility of
chronic
neuropathic
pain
KEY POINTS
■ Disorders Associated With Interstitial Cystitis
■ Allergies
■ Irritable bowel syndrome
■ Fibromyalgia
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■ Systemic lupus erythematosis
■ Inflammatory bowel disease
■ Focal vulvitis / vulvar vestibulitis
■ Sjögren’s syndrome
ETIOLOGY
to which the animal had been previously immunized resulted
in bladder inflammation (Christensen et al. 1990; Kim et al.
1992), as did a rat model of allergic cystitis using a local challenge of ovalbumin in previously sensitized rates (Ahluwalia
et al. 1998). Changes in the rat model were dependent on mast
cell degranulation and activation of sensory C fibers.
Ghoniem and coworkers (Ghoniem, Shaaban, & Clarke
1995) studied 4 female African green monkeys challenged
with intravesical acetone. Not surprisingly, they exhibited
symptoms of painful bladder syndrome. Rivas and associates
(Rivas et al. 1997) performed similar experiments using dilute
hydrochloric acid in a rat model. A rat model for neurogenic
cystitis using pseudorabies virus demonstrated that inflammatory changes in the spinal cord can result in dramatic, neurogenically mediated changes in the bladder (Doggweiler,
Jasmin, & Schmidt 1998).
The problem with all of these animal models relates to
whether or not they mirror the human disease to any great
extent. Buffington has described what appears to be a naturally occurring animal model of PBS/IC (Buffington 1994). Twothirds of cats with lower urinary tract disease have sterile
urine and no evidence of other urinary tract disorders
(Kruger et al. 1991). A portion of these cats experience frequency and urgency of urination, pain, and bladder inflammation (Houpt 1991) (Fig 10-4). Glomerulations have been
observed in the bladders of these animals. GP-51, a glycosaminoglycan (GAG) commonly found in the surface
mucin covering the mucosa of the normal human bladder and
decreased in IC, shows a decreased expression in cats with this
symptom complex (Press et al. 1995), originally termed “feline
urologic syndrome”. Bladder A_ afferents in these cats are
more sensitive to pressure changes than are afferents in normal cats (Roppolo et al. 2005). They also demonstrate an
increase in baseline nitric oxide production in smooth muscle
and mucosal strips when compared to healthy cats with evidence of altered mucosal barrier function (Birder et al. 2005).
Buffington now refers to this disorder as “feline interstitial
cystitis” (Buffington, Chew, & DiBartola 1999). It is associated
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SS. 2 patients had both the keratoconjunctivitis sicca and focal
lymphocytic sialoadenitis allowing a primary diagnosis of SS.
Only 2 patients had neither finding. He later reported an incidence of 28% of Sjögren’s in patients with interstitial cystitis
(van de Merwe, Yamada, & Sakamoto 2003). The incidence of
symptoms of PBS/IC in patients with Sjögren’s has been estimated to be up to 5% (Leppilahti et al. 2003).
A negative correlation with diabetes has been noted
(Parsons 1990; Koziol 1994).
Further epidemiologic studies are warranted, as the epidemiology of this disorder may ultimately yield as many clues
into etiology and treatment as other avenues of research.
9
It is likely that PBS/IC has a multifactorial etiology that may
act predominantly through one or more pathways resulting in
the typical symptom complex (Holm-Bentzen, Nordling, &
Hald 1990; Levander 2003; Mulholland & Byrne 1994;
Erickson 1999; Keay et al. 2004b) (Fig 10-3). There are an
abundance of theories regarding its pathogenesis, but confirmatory evidence gleaned from clinical practice has proven
sparse. Among numerous proposals that shall be further
explored in this section are “leaky epithelium”, mast cell activation, and neurogenic inflammation, or some combination
of these and other factors leading to a self-perpetuating
process resulting in chronic bladder pain and voiding dysfunction (Elbadawi 1997).
Animal Models
Until recently, lacking an easily available animal model of the
naturally occurring disease, researchers have had to devise
animal models to study isolated symptoms of PBS/IC, hoping
to uncover the root causes of the symptomatology (Ruggieri
et al. 1990). Bullock and associates (Bullock et al. 1992)
reported a mouse model in which bladder inflammation
could be induced by the injection of syngeneic bladder antigen. While demonstrating that a component in the Balb/cAN
mouse is capable of inducing a bladder-specific, adoptively
transferable, cell-mediated autoimmune response that
exhibits many characteristics of clinical IC, the model became
difficult to reproduce (Klutke, Bullock, & Ratliff 1997).
A guinea pig model in which bladder inflammation was
induced by the instillation of a solution containing a protein
Figure 10–4. Photograph of cat suffering from feline interstitial cystitis.
(Courtesy Tony Buffington.)
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
Infection
Often, a 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 (Held, Hanno, & Wein 1990). The symptom
complex looks to the patient and physician like an infectious
process (Porru et al. 2004). The epidemiology of urinary tract
infection and its predominance in women mirror the IC data
(Warren 1994). The acute to subacute onset in many patients
has fascinated clinicians who often associate an insidious
onset with a chronic condition like PBS/IC.
Reverse logic led some to suspect that antibiotics may be
instrumental in causing IC (Holm-Bentzen, Nordling, & Hald
1990). Most patients have been treated with antibiotics once
or several times before the diagnosis is made. Numerous
antibiotics, primarily in the penicillin family, can induce a cystitis (Bracis, Sanders, & Gilbert 1977; Marx & Alpert 1984;
Moller 1978; Chudwin et al. 1979; Cook, Farrar, & Kreutner
1979), but no evidence has ever been documented that these
antibiotics or the supposedly “surface
face active” nitrofurantoins
or tetracyclines have any involvement in pathogenesis
(Ruggieri, Hanno, & Levin 1987; Levin et al. 1988).
To determine whether there is an infectious cause of interstitial cystitis certain procedures are necessary (Warren 1994).
Not just urine, but bladder epithelium as well must be cultured for appropriate microorganisms, including bacteria,
viruses, and fungi. Because some organisms might be culturable yet fastidious, special culture techniques should be used.
Because some organisms in urine or tissue might be viable but
nonculturable, specific nonculture techniques for discovery
and identification should be employed. Most important, the
same procedures must be carried out in a control population.
Attempts to show an infectious etiology go back to the
dawn of the disease, but the case has never been a strong one
(Duncan & Schaeffer 1997). Hunner (Hunner 1915) (Hunner
1915) originally proposed that interstitial cystitis resulted
from chronic bacterial infection of the bladder wall secondary
to hematogenous dissemination. Harn (Harn, Keutel, &
Weaver 1973) proposed a relationship between interstitial cystitis and streptococcal and post-streptococcal inflammation.
He produced a progressive chronic inflammation in rabbit
bladders by injecting small numbers of Streptococcus pyogenes in the bladder wall. The discovery that Helicobacter
pylori is related to the pathogenesis of chronic atrophic gastritis and peptic ulcer disease, and that antibiotic treatment
can heal ulceration (Parsonnet et al. 1991; NIH Consensus
Development Panel 1994; Sung et al. 1995) has continued to
focus attention by researchers in interstitial cystitis on the
possibility that an infectious etiology is not only reasonable
but will ultimately be found. Studies of H. pylori itself have
failed to demonstrate an association with IC (Agarwal &
Dixon 2003; Atug et al. 2004; English et al. 1998; Haq, Morsy,
& Webb 2004). Wilkins (Wilkins et al. 1989) found bacteria in
catheterized urine specimens and/or bladder biopsies in 12 of
20 patients with IC. However, 8 of the isolates were fastidious
bacteria, Gardnerella vaginalis, and Lactobacillus, sp and no
controls were included in the study.
Negative studies far outnumber the positive ones. Hanash
and Pool (Hanash & Pool 1970) performed viral, bacterial and
fungal studies on 30 IC patients and failed to substantiate an
infectious etiology. Hedelin (Hedelin et al. 1983) found only 3
of 19 IC patients to have urine cultures positive for
Ureaplasma urealyticum and indirect hemagglutination antibodies to Mycoplasma hominis to be no greater than in controls. Potts cultured U. urealyticum In 22 of 48 patients with
“chronic urinary symptoms” and had great success in these
patients (none of whom had established IC) with short courses of commonly prescribed antibiotics (Potts, Ward, &
Rackley 2000). Given the history of empiric antibiotics in the
vast majority of IC patients, it is doubtful if this group represents even a small percentage of the IC diagnosed population.
Nevertheless, it illustrates that IC is a diagnosis of exclusion,
and urine culture is critical while an empiric short course of
antibiotics is certainly reasonable if the patient has not already
been treated for presumed infection. Empiric doxycycline at a
dose of 100mg twice daily for two weeks followed by 100mg
daily for two weeks has been successfully used in this manner
(Burkhard et al. 2004).
The development of highly sensitive, rapid, and specific
molecular methods of identifying infectious agents by the
direct detection of DNA or RNA sequences unique to a particular organism (Naber 1994) resulted in a flurry of activity
into the search for a responsible virus or microorganism.
Hampson (Hampson, Christmas, & Moss 1993) could find no
evidence of mycobacterial involvement in 8 cases of IC using
DNA probes. Haarala (Haarala et al. 1996) confirmed an
absence of bacterial DNA in the bladder of 11 IC patients with
no documented history of urinary tract infection. Hukkanen
(Hukkanen et al. 1996) reported an absence of adenovirus and
BK virus genomes in urinary bladder biopsies of IC patients.
Domingue’s (Domingue et al. 1995) provocative finding of
the presence of bacterial 16S rRNA genes in bladder biopsies
from 29% of IC patients but not from control bladders, and
his discovery of 0.22um filterable forms in culture of biopsy
tissue from 14 of 14 IC patients and 0 of 15 controls has never
been confirmed or repeated.
A preliminary study found a statistically significant increase
in urine PCR to C. pneumoniae major outer membrane protein gene in patients with IC as compared to controls (Franke,
Stratton, & Mitchell 1999). Other studies have shown that
similar percentages of both IC and control patient populations have non-culturable bacteria in their bladder on the
basis of polymerase chain reaction studies of bladder biopsy
specimens (Heritz et al. 1997; Keay et al. 1998a). The spirochete Borrelia burgdorferi has been found in the bladder
biopsies and urine of patients with Lyme disease, and can
cause frequency, urgency and nocturia. DNA studies have
failed to show a role for Borrelia in interstitial cystitis (Haarala
et al. 2000).
The role of infection in the pathogenesis of IC remains a
mystery (Elbadawi 1997; Elgavish et al. 1995). At this time
there is little data to support the role of an infectious etiology,
but investigators keep returning to an infectious theory. New
insights into the mechanisms by which bacteria adhere, grow
and persist in association with host tissue, and form intracel-
AL
with urinary urgency, frequency, and pain with sterile urine,
bladder mastocytosis, increased histamine excretion,
increased bladder permeability, decreased urinary GAG excretion (Buffington et al. 1996), and increased plasma norepinephrine concentrations (Buffington & Pacak 2001b).
While animal models can yield clues to etiology, all theories
must ultimately be tested in humans with the disease.
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disease as autoimmune, three types of evidence can be marshaled: 1) direct evidence from transfer of pathogenic antibody or pathogenic T cells; 2) indirect evidence based on
reproduction of the autoimmune disease in experimental animals; and 3) circumstantial evidence from clinical clues (Rose
& Bona 1993). Circumstantial evidence would include 1)
association with other autoimmune diseases in the same individual or same family; 2) lymphocytic infiltration of target
organ; 3) statistical association with a particular major histocompatibility complex haplotype; and 4) favorable response
to immunosuppression.
Circumstantial evidence by itself cannot define an autoimmune disease, and at this point the case for autoimmunity in
IC is far from clear. Three different possibilities exits: 1) IC is
caused by a direct autoimmune attack on the bladder 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 (Ochs & Tan 1997).
Silk found bladder antibodies in 9 of 20 IC patients and
none in 35 pathologic or normal control patients (Silk 1970)
(Silk 1970). Gordon found antibladder antibodies present in
biopsies from 6 of 8 IC patients and in 3 of 5 control patients
(Gordon et al. 1973). No control patient demonstrated antibodies in the muscle, while 3 of 5 IC patients with muscle in
the biopsy did so. Jokinen looked at sera from 33 IC patients
and found 28 with an antinuclear antibody (ANA) titer of
1:10 or greater, but no bladder-specific antibodies were
detected with immunofluorescence. There was poor correlation between ANA titers and symptom severity (Jokinen,
Alfthan, & Oravisto 1972). He noted that elevated antibody
titers against cell nuclei and crude kidney homogenate
decreased within 12 months after cystectomy in 3 IC patients
(Jokinen, Oravisto, & Alfthan 1973). All of this provided hints
that IC could fall into the autoimmune group of diseases.
Oravisto summarized the world literature on this idea in
1980, concluding that the chronic course of disease, the
absence of infection, the pathological findings, the occurrence
of antinuclear antibodies, and the reported responses to
steroids at that time provided strong circumstantial evidence
of autoimmunity (Oravisto 1980). He discounted the paucity
of activated lymphocytes which speak against an autoimmune
process. Studies on autoantibodies in PBS/IC have shown that
these mainly consist of antinuclear antibodies (Jokinen,
Alfthan, & Oravisto 1972)similar to the autoantibody profiles
in some systemic diseases like Sjögren’s syndrome, well known
to be of autoimmune origin (Tan 1989; Leppilahti, Tammela,
Huhtala, Kiilholma, Leppilahti, & Auvinen 2003). Mattila presented evidence of immune deposits in the bladder vascular
walls in 33 of 47 IC patients (Mattila 1982). Studying sera
from 41 patients with IC, he concluded that the classical pathway activation of the complement system was involved supporting the possibility that a chronic local immunological
process was indeed occurring (Mattila, Harmoinen, &
Hallstrom 1983). The autoantibodies tested were found to be
directed against cytoskeletal intermediate filaments. As the
autoantibodies have to gain access to intracellular structures
in order to cause in vivo deposits, primary tissue injury of
unknown etiology has to be postulated (Mattila & Linder
1984).
Anderson and colleagues (Anderson et al. 1989) studied 26
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lular pods capable of subverting host defense mechanisms and
allowing replication within epithelial cells lay the foundation
for a possible role of infection in initiating the PBS/IC pathological cascade (Kau, Hunstad, & Hultgren 2005). The
University of Maryland group proposes a model of IC in
which bladder epithelial damage such as that caused by bacterial cystitis may be the first step leading to a low-level inflammatory response we call IC (Keay & Warren 1998). Domingue
writes that “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” (Domingue & Ghoniem 1997).
If infection does play a role, it would be predicted that
appropriate treatments to minimize microbial presence in the
tissue would significantly improve the morbidity associated
with IC. Durier’s incredible series (Durier 1992) purporting
to cure 27 out of 27 IC patients with the use of up to 5 sequential antibiotics covering the anaerobic spectrum has never
been duplicated. Warren’s prospective, double-blind, placebocontrolled, randomized trial of 50 patients (Warren et al.
2000) may well prove the end of long-term empiric antibiotic
treatment in established IC. Eighteen weeks of placebo or
antibiotics (sequential doxycycline, erythromycin, metronidazole, clindamycin, amoxicillin, and ciprofloxin for 3 weeks
each) were administered. Most patients guessed the arm to
which they were assigned. Of the 25 patients in the active arm,
80% had new non-urinary symptoms perceived as sideeffects. There was minimal improvement in some patients
associated with the active arm, but the conclusion that intensive antibiotics do not represent a major advance in therapy
for IC seems well justified.
While the concept that a urinary tract infection may
trigger IC in some patients is appealing (Elbadawi
1997; Elgavish et al. 1995), it is unlikely that active
infection is involved in the ongoing pathological
process or that antibiotics have a role to play in treatment.
Autoimmunity/Inflammation
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 (Luo 2005). Inflammation results
in altered nerve growth factor content of the bladder, and
morphological changes in sensory and motor neurons innervating the bladder. Such neuroplasticity may be a possible
explanation for the association of bladder inflammation with
long term symptoms and pain after inflammation subsides
(Dupont et al. 2001).
For many years the possibility that interstitial cystitis may
represent some type of autoimmune disorder has been considered. Narrowly defined, autoimmune diseases are clinical
syndromes caused by the activation of T cells or B cells, or
both, in the absence of an ongoing infection or other discernible cause (Davidson & Diamond 2001). To establish a
11
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
components. Proliferation and cytokine production after
mitogen stimulation were the same for controls and IC
patients. Moreover, no immunologic response to IC urine by
autologous peripheral blood lymphocytes in vitro assays was
observed. Their findings cast doubt on theories suggesting
that IC is an autoimmune disease.
Numerous inflammatory mediators have been studied with
regard to their relation to interstitial cystitis (Elgebaly et al.
1992; Felsen et al. 1994; Lotz et al. 1994; Steinert et al. 1994;
Zuraw et al. 1994). Patients with PBS/IC exhibit varying
degrees of inflammation that can separate them into clusters
(Tomaszewski, Landis, Russack, Williams, Wang, Hardy,
Brensinger, Matthews, Abele, Kusek, & Nyberg 2001; Green et
al. 2004). Bladder inflammation in interstitial cystitis is categorized by elevated urinary interleukin-6 (Erickson, Belchis,
& Dabbs 1997) and activation of the kallikrein kinin system
(Rosamilia et al. 1999b). The absence of urinary interleukin1b in interstitial cystitis argues against an immunological or
autoimmune etiology of the disorder (Martins et al. 1994).
Neurogenic inflammation may play a role in the etiology, as
long-term exposure of afferent nerve terminals to inflammatory mediators can alter ion channels and result in bladder
hyperalgesia (Buffington & Wolfe 1998; Yoshimura & de Groat
1999). Substance P itself does not seem to be the single initiator of inflammation in the bladder, and its blockade does not
protect the bladder in animal models from inflammatory
responses (Luber-Narod et al. 1997). Urinary nitric oxide synthase (NOS) activity is known to be elevated in patients with
urinary infection and thought to play a role in the bladder’s
response to infection and in the inflammatory process that
follows infection. The finding that urinary NOS activity is
decreased in IC patients has puzzled researchers, but could
explain the reduction in functional bladder capacity associated with the disorder (Smith et al. 1996; Foster et al. 1997).
Urothelial cell activation in interstitial cystitis may result in
aberrant immune responses and immune activation within
the bladder wall (Liebert et al. 1993) that could relate to
pathogenesis of the disease but might not reflect initiating etiology (Ochs et al. 1994). It has been proposed that inflammatory and/or immune responses in IC could be exacerbated by
persistent activation of the nuclear factor (NF)-kb (; AbdelMageed & Ghoniem 1998; Abdel-Mageed 2003). Angiogenic
factors such as platelet-derived endothelial cell growth factor/thymidine phosphorylase and transforming growth factor-B may be involved in the inflammatory process to induce
painful symptoms in patients with interstitial cystitis or bladder carcinoma (Ueda et al. 2002).
The exact role of autoimmunity in interstitial cystitis
remains controversial (Ochs & Tan 1997). Suplatast tosilate, a
new immunoregulator, has shown efficacy in a small, uncontrolled IC study in which improvements in symptoms and
bladder capacity were correlated with changes in autoimmune
parameters (Ueda et al. 2000). Though the immune system
remains a target for therapy, no clear indication of a primary
role for autoimmunity as the cause of interstitial cystitis has
been observed (Liebert 1997).
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patients with IC and compared them to a control group of
similar age and sex with other urologic complaints. They performed a standard autoimmune profile and looked for specific antibodies to normal human bladder in the serum. Sixtyfive percent of IC patients and 36% of controls demonstrated
non-organ-specific antibodies; 40% of IC patients had antinuclear antibodies; 75% of IC patients and 40% of controls
had anti-bladder antibodies present in the serum. There was
no increase in immunoglobulin deposition in the bladder
epithelium in IC patients versus controls. Although IC
patients demonstrated a non-specific increase in antibody formation, this was not significantly different from a similar
group of other urological patients. The lack of specificity indicates the immunological findings are likely secondary to
inflammation rather than a primary etiology.
In a study looking for active immune cellular deposition in
IC patients, no statistically significant difference between controls and nonulcerative interstitial cystitis patients was identified (Harrington, Fall, & Johansson 1990). In contrast, the
ulcerative IC group had focal sheets of plasma cells, aggregates
of T cells, B cell nodules, a decreased or normal helper-to-suppressor cell ratio and suppressor cytotoxic cells in germinal
centers. Flow cytometry analysis of peripheral blood lymphocyte subsets showed increased numbers of secretory Ig positive B cells and activated lymphocytes in the nonulcerative
group, and increased numbers of secretory Ig positive cells
and activated lymphocytes in the ulcerative group. These
results may suggest a partial role for an immune mechanism
in IC. Erickson and coworkers (Erickson, Belchis, & Dabbs
1997) have also noted a major difference in inflammatory cell
types as well as clinical features in IC patients with severe
inflammation, suggesting two different patient groups with
two different underlying pathophysiologies.
Hanno and colleagues (Hanno, Levin, Monson, Teuscher,
Zhou, Ruggieri, Whitmore, & Wein 1990) found CD4 cell predominance in all layers of the bladder in IC patients.
Christmas (Christmas 1994) reported increased numbers of
CD4+ and CD8+ T cells in bladder biopsies from patients
with IC and bacterial cystitis as compared with controls.
These T cells were present in the urothelium and submucosa
but not in the detrusor. Control bladder tissue demonstrated
only CD8 cells in the urothelium and both CD4+ and CD8+
cells in the submucosa. The number of plasma cells was significantly greater in IC patients than in normal controls and
controls with bacterial cystitis.
MacDermott and colleagues (MacDermott et al. 1991b)
found a normal distribution of peripheral blood lymphocytes
in IC patients, a finding not supportive of an autoimmune
mechanism in the disease. The lamina propria showed a predominance of CD4 (helper T cells) lymphocytes over CD8
cells in both IC and other cystitis patients. The same pattern
was seen in the epithelium of patients with bacterial or
mechanical cystitis, but patients with IC had a predominance
of CD8 lymphocytes in the urothelium -- identical to controls. The findings suggest that the urothelium is not involved
in the inflammatory reaction, as is the lamina propria, making
the urothelium an unlikely source for the initiating factor.
Miller and coworkers (Miller et al. 1992) investigated the
function of peripheral blood lymphocytes from nonulcerative
interstitial cystitis patients, testing the proliferative response
and cytokine production of T cells to nonspecific mitogenic
stimulation and the proliferative response of T cells to urine
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Mast Cell Involvement
Although mast cells are thought of primarily in the context of
allergic disorders, and certain acute inflammatory responses,
these cells have also been implicated in biologic responses as
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sized in response to specific antigens. IgE binds to mast cell
receptors, and antigen binds to the IgE, leading to degranulation (Lagunoff, Martin, & Read 1983). Other triggers of mast
cell secretion include acetylcholine, anaphylatoxins, cationic
peptides like substance P, chemicals, contrast, cytokines, opioids, antihistamines, exercise, hormones, viruses, and bacterial toxins (Sant & Theoharides 1994). Mast cells promote infiltration of neutrophils, T and B lymphocytes, monocytes, and
eosinophils. T lymphocytes secrete substances capable of activating mast cells, thus perpetuating the cycle of inflammation
(Kaplan et al. 1985).
Since the presence of mast cells within the bladder wall was
first recognized (Simmons & Bunce 1958), numerous investigators have tried to determine whether there is an increase in
the number of mast cells in the bladder of patients with IC, or
differences in their location or functional state (Larsen,
Thompson, Hald, Barnard, Gilpin, Dixon, & Gosling 1982;
Kastrup et al. 1983; Fall, Johansson, & Aldenborg 1987; Feltis,
Perez-Marrero, & Emerson 1987; Lynes et al. 1987; Christmas
& Rode 1991). An increase in urothelial mast cells appears to
be part of the generalized inflammatory cell reaction regardless of etiology, and not a specific feature of IC, while the presence of increased numbers of mast cells in the detrusor is
more specific for IC. However, one study did report detrusor
mastocytosis in 64% of IC patients and 80% of a control
group with other urologic disease, with no statistically significant difference between the mean number of detrusor mast
cells in the two groups (Hanno, Levin, Monson, Teuscher,
Zhou, Ruggieri, Whitmore, & Wein 1990).
Aldenborg (Aldenborg, Fal
Fall, & Enerback 1986) reported
that mast cells are found predominantly in the detrusor muscle in patients with classic IC, but there is also a secondary
population of mast cells in the lamina propria and the bladder
epithelium, with staining characteristics distinct from those in
the detrusor. None of these epithelial mast cells were found in
controls. These findings were interpreted to indicate a
transepithelial migration of mast cells in patients with IC.
This second population of mast cells does not appear to be
involved in the non-ulcer type of IC (Aldenborg, Fall, &
Enerback 1989). This mucosal population of mast cells can
also differ from the mast cells found in deeper tissues in physiological responses and release of secretory products (Sant
1991). The “mucosal mast cells” are susceptible to aldehyde
fixation and require special fixation and staining techniques
for proper demonstration. Detrusor mast cells are not susceptible to fixation techniques. Recent studies have shown that
while all human mast cells contain the proteinase tryptase,
there is a population of mast cells that also contain the proteinase chymase. The mast cell expansion in IC involves both
types (Yamada et al. 2000). Mast cell activation is far more
pronounced in the ulcerative form which in addition displays
prominent inflammation, in contrast to non-ulcer IC, where
it is sparse. Thus, the basic pathologic processes may differ
(Peeker et al. 2000b). Because activated mast cells lose their
histologically identifiable granules once degranulation occurs,
estimates of mast cell density using standard histologic techniques may underestimate mast cell numbers (Sant &
Theoharides 1994).
Electron microscopy has confirmed that mast cells in IC are
more likely to be degranulated or activated than those found
in other conditions (Larsen, Thompson, Hald, Barnard,
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diverse as angiogenesis and wound healing, bone remodeling,
peptic ulcer disease, atherosclerosis, and reactions to neoplasms (Galli 1993). Mast cells remain one of the most enigmatic cells in the body. They secrete significant amounts of
numerous proinflammatory mediators which contribute to a
number of chronic inflammatory conditions, including stressinduced intestinal ulceration, rheumatoid arthritis, scleroderma, and Crohn’s disease. They have been described even
among the lowest order of animals, having been discovered in
the frog mesentery over 100 years ago. Their raison d’etre may
be for initiating and coordinating the host’s inflammatory and
immune responses against microbial pathogens (Abraham &
Malaviya 1997). Recently they have been implicated in a range
of neuroinflammatory diseases, especially those worsened by
stress (Theoharides 2004; Theoharides & Cochrane 2004).
These include multiple sclerosis, migraines, inflammatory
arthritis, atopic dermatitis, coronary inflammation, irritable
bowel syndrome, and PBS/IC. They may be activated through
their Fc receptors by immunoglobulins other than IgE, as well
as by anaphylatoxins, neuropeptides and cytokines to secrete
mediators selectively without overt degranulation.
Mast cells have frequently been reported to be associated
with interstitial cystitis, both as a pathogenetic mechanism
and as a pathognomonic marker (Simmons 1961; Bhone,
Hodson, Rebuck, & et al. 1962; Smith & Dehner 1972; Larsen
et al. 1982; Hofmeister et al.1997). The association of bladder
mastocytosis, interstitial cystitis, and irritable bowel syndrome
(Pang et al. 1996) and chronic urticaria (Sant et al. 1997) is
intriguing. Evidence of their importance is mounting, suggesting that they may serve as the final common pathway
through which the symptomatic condition is expressed. Mast
cells produce, among other compounds, histamine. Histamine
release in tissue causes pain, hyperemia and fibrosis; all
notable features of interstitial cystitis.
Simmons (Simmons 1961) was the first to suggest mast
cells as a cause of IC. Contribution of mast cells to the cellular infiltrate in IC (Fig 10-5) has been shown to vary from
about 20% in nonulcer IC patients to 65% in patients with
ulceration (Sant, Kilaru, & Ucci 1988; Enerback, Fall, &
Aldenborg 1989). Mast cells participate in allergic reactions
(hypersensitivity type I) during which IgE antibody is synthe-
Figure 10–5. Giemsa stain shows detrusor mastocytosis and nerve hypertrophy in interstitial cystitis. Original magnification, X400. (Courtesy of
John Tomaszewski, Hospital of the University of Pennsylvania, Department
of Pathology.)
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Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
in the bladder wall, or macrophages (Bouchelouche et al.
2001a).
Could mast cell products be useful in diagnosing IC? They
are not specific for PBS/IC, and are increased in bladder carcinoma (Serel, Soyupek, & Candir 2004). Elevated histamine
levels have been found in bladder biopsies of IC patients
(Kastrup, Hald, Larsen, & Nielsen 1983; Lynes, Flynn,
Shortliffe, Lemmers, Zipser, Roberts, & Stamey 1987;
Enerback, Fall, & Aldenborg 1989) as well as from bladder
washings (Lundeberg et al. 1993). Holm-Bentzen (HolmBentzen, Sondergaard, & Hald 1987) reported a significantly
elevated urinary excretion of 1,4-methylimidazole acetic acid,
the major metabolite of histamine. Others have found no differences between IC and controls in random spot tests of urinary histamine (Yun et al. 1992). Levels were elevated after
hydrodistention in IC patients but not in controls; a possible
consequence of hydrodistention and resultant mast cell
degranulation. El-Mansoury (El Mansoury et al. 1994) found
increased methylhistamine, a histamine metabolite, in spot
and 24 hour urine samples from IC patients as compared with
controls. While such an increase could still be interpreted as
indicating a systemic rather than a bladder syndrome, subsequent findings of elevated mast cell tryptase in the urine of IC
patients could only come from the bladder (Boucher et al.
1995). Erickson and colleagues reported that urine methylhistamine is not useful as an objective marker of response to
bladder distention or as a predictor of response to distention
or as a substitute for bladder biopsy to determine mast cell
counts (Erickson et al. 2004).
The realization that mast cells are associated with the syndrome of IC by no means diminishes the other multiple theories of causation. Their very presence could be related to
injury from any of the proposed theories of etiology, and
degranulation could likewise reflect a final common pathway
resulting in pain and frequency from multiple causes. Rickard
and Lagunoff proposed, based on results with mast cell granules and epithelial cells in tissue culture, that mast cells could
contribute to failure of epithelialization of the bladder surface
following injury by two potential mechanisms; 1) inhibition
of epithelial cell replication and 2) interference with epithelial
cell spreading, thus resulting in the “leaky epithelium” found
in some patients (Rickard & Lagunoff 1995). Mast cells may
actually be the mediator through which female hormones play
a role, accounting for the 10:1 female to male preponderance
of the disease (Vliagoftis et al. 1992; Pang et al. 1995a; Patra,
Tibbitts, & Westfall 1995; Bjorling & Wang 2001). Estradiol
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Gilpin, Dixon, & Gosling 1982; Theoharides et al. 1995;
Theoharides & Sant 1991). In at least a subpopulation of IC
patients, this may be explained by increased stimulation of
mast cells by stem cell factor (Pang, Sant, & Theoharides
1998). A chronic exposure of detrusor muscle to histamine in
IC patients is suggested by the finding that there is an impairment of the direct contractile response to histamine in detrusor muscle affected by IC in comparison to control detrusor,
suggesting a receptor desensitization (Palea et al. 1993). The
clinical relationship between an increased number of mast
cells and symptoms of IC has not been definitively established. Some studies have found no correlation (Lynes, Flynn,
Shortliffe, Lemmers, Zipser, Roberts, & Stamey 1987; HolmBentzen et al. 1987b; Dondore, Schwartz, & Semerjian 1996).
While mast cell infiltration in intestinal segments used for
augmentation has been associated with pain and failure of the
procedure (Kisman, Nijeholt, & van Krieken 1991), others
have shown that mast cell infiltration in intestine used in the
urinary tract is the norm and not pathologic (MacDermott et
al. 1990.
Many of the substances that have been shown to induce
mast cell secretion are released from neurons that innervate
the organ containing the mast cells (Christmas et al. 1990).
The capsaicin-sensitive sensory neurons that innervate the
bladder are thought to have a dual “sensory-efferent” function, in which an axon reflex-induced release of neuropeptides
results in local inflammation (Barbanti et al. 1993; Foreman
1987). Hand (Hand 1949) reported an increase in the submucosal nerve density in IC, a phenomenon confirmed by
Christmas (Christmas, Rode, Chapple, Milroy, & TurnerWarwick 1990), who showed an increase in nerve fiber proliferation in IC but not in patients with bacterial or lupus cystitis. Increased innervation by nerves releasing substances
affecting mast cells could lead to increased mast cell secretion.
Among these substances is acetylcholine. Mast cells can be
stimulated by cholinergic agonists to secrete serotonin
(Theoharides & Sant 1991). Substance P containing fibers
have been found to be increased in bladders from IC patients
and are found adjacent to mast cells (Pang et al. 1995b). In
mice, mast cells modulate the inflammatory response of the
bladder to substance P and to E coli lipopolysaccharide
(Bjorling et al. 1999).
An increase in adrenergic but not cholinergic nerves in IC
patients as compared with controls has been reported
(Hohenfellner et al. 1992). Hohenfellner and colleagues also
found increased numbers of neurons staining for vasoactive
intestinal polypeptide and neuropeptide Y (NPY), both of
which are associated with sympathetic nerves. Studies in rats
have revealed that psychological stress can activate bladder
mast cells via the action of sensory neuropeptides (Spanos et
al. 1997; Alexacos et al. 1999). Diurnal cortical variations have
been associated with symptom levels in PBS/IC (Lutgendorf
et al. 2002), and the mast cell may represent a pathway for
stress to be reflected in bladder symptomatology.
Mast cells can alter their environment by regulating tissue
gene expression (Saban et al. 2001). The finding of increased
synthesis of urinary leukotriene E4 in patients with IC and
detrusor mastocytosis when compared with healthy controls
suggests that cysteinyl containing leukotrienes are involved in
the inflammatory reaction observed in the urinary bladder of
patients with IC and may be produced from tissue mast cells
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KEY POINTS
To summarize, much important IC research has centered on the mast cell. Mast These cells are strategically localized in the urinary bladder close to blood vessels, lymphatics, nerves and detrusor smooth muscle
(Saban, Keith, & Bjorling 1997). Studies to date
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 (Elbadawi & Light
1996; Filippou, Sant, & Theoharides 1999) (Elbadawi
& Light 1996; Filippou, Sant, & Theoharides 1999).
Bladder Glycosaminoglycan Layer and
Epithelial Permeability
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Until the early 1970's, most investigators thought that the
major barrier to free flow of urinary constituents was at the
level of the epithelial cells. Tight junctions between urothelial
cells, specialized “umbrella cells” lining the surface, and direct
bactericidal activity of the vesical mucosa were thought capable of defense of the internal milieu from bacteria, molecules,
and ions in the urine (Ratliff, Klutke, & McDougall 1994).
Staehelin and colleagues proposed that lipid and other
hydrophobically bonded materials were important in any barrier to permeability in the luminal membrane because permeants leaked through the interplaque regions if the particles
alone limited transport (Staehelin, Chalpowski, & Bonneville
1972). It has been shown that inflammation of the underlying
muscle and lamina propria can disrupt the bladder permeability barrier by damaging tight junctions and apical membranes and causing sloughing of epithelial cells. Leakage of
urinary constituents through the damaged epithelium may
then exacerbate the inflammation in the deeper layers (Lavelle
et al. 1998; Lavelle et al. 2000).
It was Parsons who hypothesized and popularized the concept that interstitial cystitis in a subset of patients is the result
of some defect in the epithelial permeability barrier of the
bladder surface glycosaminoglycans (Parsons & Hurst 1990).
The major classes of glycosaminoglycans (GAGs) include
hyaluronic acid, heparin sulfate, heparin, chondroitin 4-sulfate and chondroitin 6-sulfate, dermatan sulfate, and keratan
sulfate. These carbohydrate chains, coupled to protein cores,
produce a diverse class macromolecules, the proteoglycans
(Trelstad 1985). GAGs exist as a continuous layer on the bladder urothelium (Dixon et al. 1986; Cornish et al. 1990). Except
heparin, all the other types of GAGs have been found on the
bladder surface (Ruoslahti 1988). The GAG layer functions as
a permeability and antiadherence barrier. When impaired, its
functions can be duplicated by exogenous GAG (Hanno, Fritz,
& Wein 1978). In the absence of this protective layer in the
urinary bladder, its susceptibility to infection would increase,
and the production of nitric oxide in the urothelial cells, and
of substance P in the intra-epithelial afferent C-fiber terminals, increases. Consequently, the permeability of both the
urothelium and the blood vessels in the mucous membrane
increases, and the blood flow slows due to vasodilatation
(Hohlbrugger 1999).
Parsons and Hurst reported a lower excretion of urinary
uronic acid and glycosaminoglycans in IC patients than in
normal volunteers and hypothesized that a leaky transitional
epithelium might be absorbing these substances to its surface
(Parsons & Hurst 1990). The data are interesting in that one
might expect urinary GAG to increase with injury to the bladder and decrease with resolution (Uehling et al. 1988)
(Uehling et al. 1988). The San Diego group (Lilly & Parsons
1990; Parsons et al. 1990) went on to show experimentally that
one can damage the GAG layer with protamine sulfate with
resultant back-diffusion of urea through the bladder lumen,
and that this urea loss can be prevented with a bladder instillation of exogenous GAG (heparin). By placing a solution of
concentrated urea into the bladder of IC patients and measuring absorption versus controls, Parsons found support for
his theory in patients with interstitial cystitis (Parsons, Lilly, &
Stein 1991). The rationale of the epithelial permeability
school is nicely summarized in four publications (Parsons
1993; Parsons 1994; Hurst, Roy, & Parsons 1997; Hohlbrugger
& Riedl 2000) and provides a comprehensive, if somewhat
imperfect, theory of the disorder.
Support for an epithelial abnormality from a different perspective has come from Bushman who found aneuploid DNA
profiles on barbotage specimens from interstitial cystitis
patients that may signal an underlying abnormality of the
epithelial cell population in some patients with IC (Bushman
et al. 1994). Wilson and colleagues identified a loss of type IV
collagen in the urothelial basement membrane in 5 of 11 IC
patients (Wilson et al. 1995). Hurst’s group studied bladder
biopsies of IC patients and controls and concluded that there
is a deficit of bladder luminal and basal proteoglycans associated with the disorder. The basal abnormality may reflect an
altered urothelial differentiation program (Hurst et al. 1996).
In a later study IC bladder biopsies showed abnormalities in
24 of 27 patients when examined by immunohistochemical
assessment of E-cadherin, ZO-1, uroplakin and chondroitin
sulfate (Slobodov et al. 2004). Erickson and coworkers measured a glycoprotein (epitectin) in the urine of IC patients and
found a decrease compared to a control population, although
a significant overlap was detected (Erickson et al. 1996).
Buffington and Woodworth gave 6 IC patients and 6 controls
oral fluorescein dye. IC patients had higher levels of fluorescein in their plasma and lower urinary excretion of the dye,
suggesting altered membrane permeability and increased fluorescein reabsorption in the bladder wall of IC patients
(Buffington & Woodworth 1997). Erickson and colleagues
compared urinary levels of hyaluronic acid in IC patients and
controls, reporting higher urinary hyaluronic acid in the
patient group, possibly accounted for by leakage of this GAG
across the epithelium (Erickson et al. 1998).
Further data for an abnormal surface mucin came from
Moskowitz and colleagues who studied biopsies from 23 IC
patients with regard to the presence of a glycoprotein component of the surface mucin referred to as GP1 and compared
the results to 11 normal controls. Qualitative GP1 changes in
a majority of IC patients were identified. GP1 reactivity was
noted in all controls, but was absent in 35% of IC patients and
diminished in 61% (Moskowitz et al. 1994). This study may
provide evidence of an abnormal bladder urothelium, but the
effects of bladder distention in the IC group is unknown and
may have contributed to the results. There were no pathologic controls used, and no attempt was made to correlate GP1
reactivity with IC symptoms (Messing 1994). Castration in
female rabbits is associated with bladder mucosal changes
resulting in increased mucosal permeability (Parekh et al.
2004). Birder and colleagues have shown that feline interstitial
cystitis results in increased baseline production of nitric oxide
due to inducible nitric oxide synthase (Birder, Wolf-Johnston,
Buffington, Roppolo, de Groat, & Kanai 2005). These changes
in transmitter release may have a role in altering mucosal barrier properties.
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augments the secretion of mast cell histamine in response to
substance P. It has been proposed that the symptoms of IC
may depend on an imbalance of the relative number of estrogen receptors to progesterone receptors on bladder mast cells
(Letourneau et al. 1996).
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Dixon, Holm-Bentzen, Gilpin, Gosling, Bostofte, Hald, &
Larsen 1986; Johansson & Fall 1990; Ruggieri, Steinhardt, &
Hanno 1991). Nickel ‘s group (Nickel, Emerson, & Cornish
1993) reported sophisticated electron micrography using a
specific anti-mucus, antisera stabilization technique to study
the ultrastructural morphological appearance of the GAG. No
significant difference in the morphological appearance of the
mucus or GAG layer was noted in IC versus controls. Urinary
chondroitin sulfates, heparan sulfate and total sulfated glycosaminoglycans normalized to creatinine are not altered in
interstitial cystitis (Erickson et al. 1997). While an increased
ratio of total GAGs to sulfated GAGs in IC may indicate an
altered GAG layer, whether it reflects a cause or is a result of
the primary pathologic process (s) is unknown (Wei et al.
2000). That leaves one to postulate an as yet unknown functional abnormality, rather than GAG deficiency, to account for
any increase in permeability.
Chelsky and coworkers measured bladder permeability in
IC using direct measurement by transvesical absorption of
99mtechnetium-diethylenetriaminepentaacetic acid (DTPA).
While some IC patients had a more permeable bladder than
others, the same was true for normal volunteers. Increased
permeability in the IC group could not be demonstrated.
However, 3 IC patients had marked absorption of DTPA and
may represent a subpopulation of patients with increased
epithelial permeability (Chelsky et al. 1994). Intravesical
instillation of 10% and 20% ethanol in rabbits was reported to
be a reliable quantitative measure of bladder hyperpermeability by the San Diego group (Monga, Percival, & Zupkas 2001),
and subsequently failed to demonstrate bladder permeability
in humans with interstitial cystitis (Gordon, Parsons, &
Monga 2003).
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Purportedly strong evidence for a population with mucosal leak has been reported (Parsons et al. 1994b). Parsons
placed water or 0.4M potassium chloride (KCl) intravesically
into normal volunteers and IC patients. Water did not provoke pain in either group, but KCl provoked the symptom in
4.5% of normals and 70% of IC patients. Symptomatic
responses were reduced in patients on heparinoid therapy.
Similar findings occur in patients with radiation cystitis
(100%) (Parsons et al. 1994c), urinary infection (100%)
(Parsons et al. 1998), detrusor instability (25%) (Parsons,
Greenberger, Gabal, Bidair, & Barme 1998), “urethral syndrome” (55%) (Parsons, Zupkas, & Parsons 2001), and greater
than 80% of women with endometriosis, vulvodynia, and
pelvic pain (Parsons et al. 2001; Parsons et al. 2002b). Eightyfour per cent of men with prostatitis also have a positive test
(Parsons & Albo 2002). The poor specificity of the potassium
test does not suggest that it is providing unequivocal evidence
of a permeability dysfunction. As it is known that the normal
bladder epithelium can never be absolutely tight, and there is
always some leak, however small (Hohlbrugger 1997), it is
conceivable that the findings of pain with KCl are related to a
hypersensitivity of the sensory nerves in this condition, rather
than to pathologic epithelial permeability, at least in some
patients. In fact, KCl administered intravesically to cats with
feline interstitial cystitis seems to inhibit afferent firing of
peripheral A_ fibers. Heightened sensitivity of afferent nerve
fibers can explain potassium chloride results without necessarily evoking increased permeability (Lutgendorf & Kreder
2005; Roppolo, Changfeng, Booth, Buffington, de Groat, &
Birder 2005). Intravesical administration of KCl has since
been proposed as a diagnostic test for IC (Parsons,
Greenberger, Gabal, Bidair, & Barme 1998) (see below).
How central abnormal epithelial permeability is to IC is,
however, by no means clear. Tamm-Horsfall protein (THP), a
high-molecular-weight glycoprotein synthesized exclusively
by the ascending loop of Henle and the distal tubule of the
kidney, has been studied as a potential marker of urothelial
permeability. Fowler provided graphic data that the urothelium might be leaky in IC. With immunohistochemical techniques his group assayed the bladder biopsies of 14 IC patients
and 10 normal controls for intraurothelial THP to assess indirectly the in vivo permeability of the urothelium. Eight pathologic controls were also assessed. Ten of 14 IC patients versus
1 of 18 controls demonstrated intraurothelial THP (Fowler, Jr.
et al. 1988). Serum THP autoantibody and is higher in PBS/IC
patients versus controls (Neal, Jr., Dilworth, & Kaack 1991). It
is known that excretion rates of THP vary widely, even in
repeat samples taken from the same individual (Reinhart et al.
1990). Subsequent studies in IC have failed to show differences in the presence of intraurothelial THP in the IC population versus controls, andnor in antibody reactivity to THP
(Stone et al. 1992; Stein et al. 1993). Bade and coworkers failed
to find THP in the bladder tissue from 10 IC patients (Bade et
al. 1996). Others have suggested that when THP is seen in
bladder tissue, it is an incidental finding of no clinical significance. The finding of intraurothelial THP has not been shown
to be a harbinger of IC or any other bladder disorder (Truong,
Ostrowski, & Wheeler 1994).
Finally, we must look at a body of literature that has failed
to find GAG abnormality or hyperpermeability. Ultrastructural, biochemical, and functional studies of bladder
GAG have not supported this theory (Collan et al. 1976;
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Neurobiology
Neuropeptides present in primary afferents and the dorsal
horn of the spinal cord have an important role in the mediation of nociceptive input under normal conditions. Under
KEY POINTS
Overall, it does seem that there is a population of IC
patients with increased epithelial permeability., but
the issue is far from closed. Increased mucosal permeability is nonspecific and a consequence of bladder
inflammation, and also occurs with cyclophosphamide-induced bladder injury, bacterial infection,
and cystitis following intravesical challenge with antigen after sensitization (Engelmann, Burger, & Jacobi
1982; Kim, Levin, Wein, & Longhurst 1992). It may
also be a consequence of aging itself (Jacob et al.
1978). Whether this represents a primary cause of IC
or merely reflects the result of an as-yet-unidentified
source of inflammation is unclear. Treatments that
tend to damage GAG, including transurethral resection and laser of ulcerated areas, bladder distention,
silver nitrate administration, and chlorpactin administration and the organic solvent dimethylsulfoxide have
all been used with varying results to treat IC.
Increased permeability and epithelial dysfunction
must be only a part of the story.
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Thuroff, & Tanagho 1992) suggested that IC is associated with
increased sympathetic outflow into the bladder and altered
metabolism of vasoactive intestinal polypeptide and neuropeptide Y. Neuropeptide Y (NPY) inhibits bladder afferents
and therefore may be involved in autonomic disturbances
affecting the bladder. Elevation of urinary catecholamines in
IC patients and plasma catecholamines in cats with feline
interstitial cystitis has been observed (Buffington & Pacak
2001a; Stein, Torri, & Parsons 1999) (Buffington & Pacak
2001a; Stein, Torri, & Parsons 1999), as has an increased density and number of nerve fibers immunoreactive for tyrosine
hydroxylase in IC patients (Peeker et al. 2000a) (Peeker et al.
2000a). Whether these changes reflect a cause of IC or are
merely the result of long-standing intense pain and a severely
pathologic voiding pattern is unknown.
Galloway (Galloway, Gabale, & Irwin 1991) proposed that
the changes in IC may be explained by an increase in sympathetic discharge, analogous to that seen in reflex sympathetic
dystrophy (RSD) of limbs. The pathology in RSD is the development of abnormal synaptic activity between sensory afferent and sympathetic efferent neurons. Nerve cells in the spinal
cord become hypersensitive to sensory input, and this sustains
abnormal sympathetic outflow and corresponding vasomotor
disregulation. The excess sympathetic outflow leads to constriction of blood vessels and tissue ischemia, setting up further sensory changes and perpetuating the cycle. In RSD, there
is usually a trigger event leading to these changes. With the
acute phase of RSD, regional signs of inflammation are evident in the affected extremity. One school of thought believes
an inflammatory response to an injury initiates RSD.
Increased capillary permeability is a direct result (Goris & Jan
1998). Perhaps a urinary infection could trigger such a pathologic cycle in some IC patients?
Herbst (Herbst, Baumrucker, & German 1937) produced
bladder lesions in a dog resembling the ulceration of IC by ligating the blood vessels to the posterior bladder wall and
infecting the area with Streptococcus viridans. Studies using
laser doppler flowmetry have shown that when the bladder is
distended under anesthesia, blood flow increases in control
patients to a statistically significant degree as compared with
IC patients (Irwin & Galloway 1993; Pontari, Hanno, &
Ruggieri 1999). Another study has purported to show that
topical heparin therapy can normalize urothelial permeability
and vesical blood flow in interstitial cystitis (Hohlbrugger et
al. 1998). Decreased microvascular density has been described
in the suburothelium but not in the deeper mucosa in bladder
biopsies of women with IC (Rosamilia et al. 1999a).
Hyperbaric oxygen has been suggested to be effective in the
treatment of PBS/IC (van et al. 2004b) (van et al. 2004b) as
well as radiation-induced cystitis (Weiss & Neville 1989).
If lumbar sympathetic blocks can decrease the pain of IC, a
role of the sympathetic nervous system in IC pathogenesis is a
reasonable supposition (Irwin, Hammonds, & Galloway 1993;
Doi et al. 2001). Buffington has demonstrated an increase in
sympathetic activity in cats with feline interstitial cystitis
(Buffington & Pacak 2001b; Buffington, Teng, & Somogyi
2002). Similar findings have been reported in a small study of
IC patients (Dimitrakov et al. 2001) and sympathetic activity
may be an underlying common denominator in many disorders associated with PBS/IC (Buffington 2004).
Nevertheless, no studies performed to date can say any case
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pathological conditions, such as chronic inflammation or following peripheral nerve injury, the production of peptides
and peptide receptors is dramatically altered, leading to a
number of functional consequences (Wiesenfeld-Hallin & Xu
2001). Inflammatory painful stimuli, especially if repeated,
can chronically alter innervation, central pain-processing
mechanisms, and tissue responses (Steers & Tuttle 1997). It
has been known for some time that the sensory nervous system can generate some of the manifestations of inflammation
(Foreman 1987; Dimitriadou et al. 1991; Dimitriadou et al.
1992). Activation of capsaicin sensitive afferent neurons locally and centrally may be involved in stress related pathological
changes in the rat bladder (Ercan, Oktay, & Erin 2001).
Activation of sensory nerves, specifically pain fibers, is known
to trigger neurogenic inflammation through release of neuropeptides such as substance P, neurokinin A, and calcitonin
gene related protein, and subsequent increase in vascular permeability, with leukocyte adhesion and tissue edema. The
neuropeptide mediators have been shown to also cause
degranulation of mast cells with release of additional potent
mediators of inflammation and to lead to injury and increased
permeability of epithelial surfaces (Elbadawi & Light 1996).
An increase in nerve fibers within the suburothelium and
detrusor muscle in ulcerative IC has been noted (Lundeberg,
Liedberg, Nordling, Theodorsson, Owzarski, & Ekman 1993).
A correlation was found between the number of nerve fibers
and numbers of mast cells as well as between the number of
nerve fibers and the amount of histamine. Consolidating the
leaky urothelium theory and mast cell activation, neurogenic
inflammation is an attractive proposal for etiology, and can
readily accommodate infectious, immunologic, and autoimmunologic mechanisms as factors (Elbadawi & Light 1996).
Harrison (Harrison, Ferguson, & Hanley 1990) proposed
that small diameter sensory nerves in the bladder wall may
have a role in the transmission of the sensation of pain and in
the triggering of inflammatory reactions rather than forming
the afferent limb of the micturition reflex. Abelli (Abelli et al.
1991) demonstrated in the rat urethra that mechanical irritation alone can cause neuropeptide release from peripheral
capsaicin-sensitive primary afferent neurons resulting in neurogenic inflammation. Extracellular adenosine triphosphate
can act through the purinergic receptor subtype P2X3 to
transmit a pain signal to the central nervous system. These
subunits expressed by cultured interstitial cystitis bladder
urothelial cells are upregulated during in vitro stretch and
may phenotypically mimic sensory neurons (Sun & Chai
2004).
Several pieces of additional information support a theory
of neurogenic inflammation. Levels of nerve growth factor are
elevated in bladder biopsies of IC patients (Lowe et al. 1997).
Studies in rats using pseudorabies virus clearly show that
bladder inflammation can be induced from a somatic structure through a neural mechanism and that central nervous
system dysfunction can bring about a peripheral inflammation (Doggweiler, Jasmin, & Schmidt 1998; Jasmin et al. 1998).
Pelvic nerve stimulation in the rat increases urothelial permeability that is antagonized by capsaicin indicating both an
efferent effect of afferent nerves and afferent mediated neuroepithelial interaction (Lavelle et al. 1999).
Numerous studies indicate increased sympathetic activity
in IC. Hohenfellner (Hohenfellner, Nunes, Schmidt, Lampel,
17
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
KEY POINTS
Neurogenic inflammation may be the cause of some
cases of IC, or may be the result of other initiating etiologic events. It is not incompatible with the central
role of the mast cell, or with the leaky epithelium theory. It conceivably could result in the appearance of
autoimmune phenomena or result from an episode of
infection. The central nervous system may also be
implicated in disregulation of the pelvic floor resulting in chronic pelvic pain and contributing to IC
(Zermann et al. 1999), and perhaps in the rare cases of
IC that chronologically seem to relate to trauma or
pelvic surgery (Zermann et al. 1998). It is an etiologic
theory that provides fertile ground for new treatment
possibilities.
gic, or immunologic means. The substance in the urine may
be a naturally occurring one -- a substance that acts as an initiator only in particularly susceptible individuals -- or may act
like a true toxin, gaining access to the urine by a variety of
mechanisms or metabolic pathways (Wein & Broderick 1994).
Clemmensen (Clemmensen et al. 1988) noted that 8 of 11 IC
patients had positive skin reactions to patch tests with their
own urine. Immediate reactions were not observed and the
histology suggested a toxic rather than an allergic reaction.
Lynes was unable to find a urinary myotropic substance
unique to interstitial cystitis patients (Lynes, Shortliffe, &
Stamey 1990). The San Diego group found IC urine to result
in higher cell death of cultured transitional cells than normal
urine, suggesting a toxic compound in the urine of some IC
patients (Parsons & Stein 1990). They identified heat labile,
cationic components of low molecular weight that bind to
heparin, and that when separated from the bulk of urinary
wastes, are cytotoxic to urothelial cells as well as underlying
smooth muscle cells (Parsons et al. 2000). They reported a
12% increase in 72 kDa stress protein in cells treated with
urine from IC patients compared to controls (Ito et al. 1998).
Others have not been able to demonstrate in-vitro cytotoxicity (Beier-Holgersen et al. 1994) or immunohistochemical
changes in the nociceptive centers in the spinal cord or bladder wall when IC urine was compared to control urine
(Baykara et al. 2003). Efforts to induce an IC-like picture in
the rabbit bladder from exposure to urine of IC patients have
failed to demonstrate conclusive changes (Perzin, Hanno, &
Ruggieri 1991; Ruggieri et al. 1993; Kohn et al. 1998).
Increased levels of soluble mediators associated with activation of sensory neurons and/or mast cells have been found in
the urine of both IC and bladder cancer patients (Okragly et
al. 1999).
Circumstantial evidence for the toxicity of IC urine is suggested by the failure of substitution cystoplasty and continent
diversions in some of these patients because of the development of pain or contraction of the bowel segment over time
(Nielsen et al. 1990; Baskin & Tanagho 1992; Trinka et al.
1993; Lotenfoe et al. 1995), and the histologic findings similar
to IC found to occur in bowel used to augment the smallcapacity IC bladder (McGuire, Lytton, & Cornog, Jr. 1973;
Singh & Thomas 1996). Intestinal mucosa in contact with
urine undergoes progressive changes as long as 3 years after
surgery and the significance of the histologic IC-like changes
AL
of IC is related to the syndrome of reflex sympathetic dystrophy (Ratliff, Klutke, & McDougall 1994). No single test can be
used to exclude sympathetically maintained pain and there are
no clear symptoms that predict sympathetically mediated
pain (Baron 2000). In the animal model, bladder ischemia is
associated with detrusor overactivity or impaired detrusor
contraction, not sensory urgency (Azadzoi et al. 1999). Those
patients with RSD who have voiding symptoms rarely have a
picture that would be confused with IC (Chancellor et al.
1996).
Before leaving the neurogenic theory of etiology, it is
important to note that the nervous system itself almost surely
contributes to the chronic nature of this pain syndrome,
regardless of initiating etiology (Vrinten et al. 2001).
Repetitious stimulation of a peripheral nerve, at sufficient
intensity to activate C fibers, results in a progressive buildup
of the magnitude of the electrical response recorded in the
second order dorsal horn neurons. This “wind-up” phenomenon is central to the concept of chronic pain. Biochemically it
is dependent on activation of N-methyl-D aspartate (NMDA)
receptors in the spinal cord (Bennett 1999). With persistent
NMDA receptor activation, spinal cord cells undergo trophic
changes, and the pain resulting from subsequent stimulation
becomes exaggerated and prolonged. This “pain memory” in
the spinal cord may be what causes IC patients to become
refractory to different therapies (Brookoff 1997). NMDAreceptor-driven formation of new connections in the spinal
cord may account for the expansion of the pain field.
Upregulation of the CNS and augmented sensory processing has been referred to as nonnociceptive pain (NNP)
(Bennett 1999). The four characteristic features of NNP
would seem to apply very well to the clinical syndrome of IC
(Table 10-3). Chronic neuropathic pain may continue after
the resolution of tissue damage and persist on the basis of a
maladaptive mechanism (Urban, Nagy, & Bevan 2002).
Burnstock’s observation (Burnstock 1999) that adenosine
triphosphate (ATP) has a role in mechanosensory transduction by the epithelial lining of hollow viscus organs such as
bladder has been followed up by Sun and colleagues. Stretched
epithelial cells lining hollow organs
organs release ATP which acts on
purinergic nociceptive receptors on subepithelial sensory
nerve terminals. ATP was significantly elevated in the urine of
PBS/IC patients, and the stretch activated release of ATP was
augmented in IC urothelium (Sun et al. 2001).
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18
Urine Abnormalities
Current theories of pathogenesis generally involve access of a
component of urine to the interstices of the bladder wall,
resulting in an inflammatory response induced by toxic, allerTable 10-3. Non-Nociceptive Pain: Characteristic
Clinical Features
1. The description of the pain seems inappropriate in comparison with
the degree of tissue pathology, or no tissue pathology may be discernible.
2. Noxious stimuli result in a pain experience that is greater and more
unpleasant than would normally be expected (hyperalgesia).
3. Normally non-noxious stimuli may now result in pain (allodynia).
4. The extent of the pain boundary is greater than would be expected
on the basis of the site of the original tissue pathology.
Antiproliferative Factor (APF)
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The finding that cells from the bladder lining of normal controls grow significantly more rapidly in culture than cells from
IC patients (Keay et al. 1996) led Keay and associates at the
University of Maryland to the discovery of an Antiproliferative factor (APF) produced by the urothelium of IC
patients. Normal bladder cells were cultured in the presence of
urine from patients with IC, asymptomatic controls, bacterial
cystitis, and vulvovaginitis. Only urine from IC patients inhibited bladder cell proliferation (Keay et al. 1998b). The presence of APF was found to be a sensitive and specific biomarker for IC (Keay et al. 2001) (Table 10-4). It was found in bladder urine but not in renal pelvic urine of IC patients, indicating production by the bladder urothelial cells (Keay et al.
1999). Subsequent studies indicated that APF is associated
with decreased production of heparin binding epidermal
growth factor-like growth factor (HB-EGF) (Keay et al. 2000;
Keay et al. 2003b). APF activity was related to increased production of epidermal growth factor (EGF), insulin-like
growth factor-1, and insulin-like growth factor binding protein-3 by the bladder cells from IC patients but not by the cells
from healthy bladders. Studies of IC patients and asymptomatic controls showed urine levels of APF, HB-EGF, and EGF
to reliably separate out IC from controls (Keay, Zhang,
Shoenfelt, Erickson, Whitmore, Warren, Marvel, & Chai 2001;
Erickson et al. 2002).
APF levels in the urine were found to discriminate between
men with IC versus those with chronic pelvic pain syndrome
(CPPS) or nonbacterial prostatitis (Keay et al. 2004a). APF
activity dropped significantly in IC patients within 2 hours
after hydrodistention (Chai et al. 2000b) and after 5 days of
sacral neuromodulation (Chai et al. 2000a). Cell culture studies showed that APF actually caused decrease in HB-EGF and
TABLE 10-4. Prevalence of Urine Antiproliferative
Factor Activity in Interstitial Cystitis Patients
and Control Groups1
Groups
Number of Patients
Positive/Total
KEY POINTS
Antiproliferative Factor is a frizzled 8 protein produced by bladder uroepithelial cells of PBS/IC
patients. It inhibits bladder cell proliferation and
appears to be a sensitive and specific biomarker for
interstitial cystitis. Initial studies suggest it can differentiate chronic pelvic pain syndrome in men/chronic
nonbacterial prostatitis from PBS/IC. It causes a
decrease in heparin binding epidermal growth factorlike growth factor and an increase in epidermal
growth factor. It may ultimately unlock the etiology of
the syndrome and could provide avenues for development of future therapies.
% Positive
Other Potential Etiologies
Patients
Interstitial cystitis
206/219
94
Controls
Asymptomatic
Overactive bladder
Bacterial cystitis
Microscopic hematuria
Stress incontinence
Neurogenic bladder
Benign prostatic hypertrophy
Nonbacterial prostatitis
Vulvovaginitis
Miscellaneous
10/113
2/32
7/58
2/19
1/10
0/11
1/14
1/16
0/12
1/16
9
6
12
10
10
0
7
6
0
6
Keay, S. K., Zhang, C. O., Shoenfelt, J., Erickson, D. R., Whitmore, K.,
Warren, J. W. et al.: Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor as urine markers for interstitial cystitis. Urology,
57: 9, 2001.
1
increase in EGF, mirroring the differences in urine levels of
these growth factors between IC patients and controls, and
suggesting that APF is the primary abnormality (Keay, Zhang,
Shoenfelt, & Chai 2003b).
While APF may prove to be a useful marker for PBS/IC, it
may also unlock the etiology of the syndrome. It has been
hypothesized by Keay and colleagues that PBS/IC may result
from an inhibition of bladder epithelial cell proliferation
caused by the APF, which is mediated by its regulation of
growth factor production from bladder cells (Keay et al.
2003a). Conceivably, any of a variety of injuries to the bladder
(infection, trauma, and overdistention) in a susceptible individual may result in PBS/IC if APF is present and suppresses
production of HB-EGF (Keay & Warren 1998). Theoretically,
if production of APF could be “turned off ” by genetic techniques, or its effects were nullified by exogenous HB-EGF
growth factor, the clinical syndrome might be prevented.
APF has been purified (Fig 10-6) and proved to be a frizzled
8 protein that belongs to a newly discovered family of proteins
which seem to be important in the development of nerve tissues, skin, and the lining of organs (Keay, Szekely, Conrads,
Veenstra, Barchi, Jr., Zhang, Koch, & Michejda 2004b). Studies
are ongoing to confirm the research by Dr. Keay and colleagues and expand on its significance in diagnosis and development of a rational treatment approach (Rashid et al. 2004)
(Rashid et al. 2004).
AL
has been questioned (MacDermott, Charpied, Tesluk, & Stone
1990; Davidsson et al. 1996).
19
Various other etiologic theories have been proposed (Ratliff,
Klutke et al. 1994), but none has received much scientific support. Voiding almost hourly, always having to be aware of how
far the nearest restroom facilities are, and suffering constant
pain would be expected to lead to psychological stress.
However, could there be individual differences in the propensity to develop interstitial cystitis that result from a disregulation of anxiety and mood (Nesse 1999; Bodden-Heidrich
2004)? There is no data currently to suggest that stress initiates
the chronic syndrome of interstitial cystitis, although it certainly can increase symptom severity (Lutgendorf et al. 2000).
Cats restricted to indoor living are 5 times more likely to have
urinary problems as cats allowed outdoors (Buffington 2002).
Female patients with PBS/IC have been shown to have
increased heart rate at baseline and throughout a laboratory
mental stress challenge, but did not demonstrate greater auto-
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
MEWGYLLEVT SLLAALALLQ RSSGAAAASA KELACQEITV PLCKGIGYNY TYMPNQFHD
TQDEAGLEVH QFWPLVEIQC SPDLKFFLCS MYTPICLEDY KKPLPPCRSV CERAKAGCAP
LMRQYGFAWP DRMRCDRLPE QGNPDTLCMD YNRTDLTTAA PSPPRRLPPP PPGEQPPSGS
GHGRPPGARP PHRGGGRGGG GGDAAAPPAR GGGGGGKARP PGGGAAPCEP
GCQCRAPMVS VSSERHPLYN RVKTGQIANC ALPCHNPFFS QDERAFTVFW IGLWSVLCFV
STFATVSTFL IDMERFKYPE RPIIFLSACY LFVSVGYLVR LVAGHEKVAC SGGAPGAGGA
GGAGGAAAGA GAAGAGGP GGRGEYEELG AVEQHVRYET TGPALCTVVF LLVYFFGMAS
SIWWVILSLT WFLAAGMKWG NEAIAGYSQY FHLAAWLVPS VKSIAVLALS SVDGDPVAGI
CYVGNQSLDN LRGFVLAPLV IYLFIGTMFL LAGFVSLFRI RSVIKQQDGP TKTHKLEKLM
IRLGLFTVLY TVPAAVVVAC LFYEQHNRPR WEATHNCPCL RDLQPDQARR PDYAVFMLKY
FMCLVVGITS GVWVWSGKTL ESWRSLCTRC CWASKGAAVG GGAGATAAGG
GGGPGGGGGG GPGGGGGPGG GGGSLYSDVS TGLTWRSGTA SSVSYPKQMP LSQV
OH OH
OH
OH
CO2H OH
HO
O
O
O
O
O
AcHN
OH HO
HO
AcNH
O
Figure 10–6. Composition and structure of
antiproliferative factor (APF). (from Keay SK,
Szekely Z, et.al: An antiproliferative factor from
interstitial cystitis patients is a frizzled 8 protein-related sialoglycopeptide. Proc Natl Acad
Sci U S A, 101:11803,2004.)
O
N
OO
N
H
H
N
O
H
N
O
N
H
O
H
N
O
N
H
COOH
O
AL
N
NH2 H
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SECTION III
20
nomic reactivity to stress (Lutgendorf et al. 2004). Until stress
can be shown to produce PBS/IC de novo in humans, it is just
as reasonable to speculate that the stress is a result of the syndrome as a primary etiology for it.
Speculation that abnormalities in or obstruction of lymphatics or vascular structures is causative has never been
borne out. The fact that some of these patients have had hysterectomy probably relates more to the attempt of the physician to treat chronic pelvic pain, than post-surgical change
causing the IC syndrome (Chung 2004).
The knowledge that there is at least a 5:1 female to male
preponderance immediately makes the role of the hormonal
milieu potentially important (Bjorling & Wang 2001).
Paradoxically, it is known that estrogens can control hematuria in hemorrhagic cystitis, perhaps by decreasing the
fragility of the mucosal microvasculature of the bladder (Liu
et al. 1990). Estradiol augments while the estrogen receptor
blocker tamoxifen inhibits mast cell secretion (Vliagoftis,
Dimitriadou, Boucher, Rozniecki, Correia, Raam, &
Theoharides 1992). Bladder mast cells express high-affinity
estrogen receptors, and there is a higher number of such cells
present in patients with IC compared with controls. While this
may help explain why IC is so common in women, the hormonal role can only account for the propensity of IC to occur
in females, not the ultimate etiology.
Pelvic floor dysfunction has been associated with PBS/IC
for many years (Schmidt & Vapnek 1991), and uncontrolled
trials suggest that treatment of the pelvic floor can be effective
in ameliorating symptoms (Lilius, Oravisto, & Valtonen 1973;
Doggweiler-Wiygul, Blankenship, & MacDiarmid 2001;
Holzberg et al. 2001; Weiss 2001; Doggweiler-Wiygul &
Wiygul 2002; Oyama et al. 2004). Speculation that abnormalities of the pelvic floor muscular function may contribute to
the etiology of some cases of the chronic pelvic pain syndrome in men are well accepted (Segura, Opitz, & Greene
1979; Schmidt & Vapnek 1991; Zermann, Ishigooka,
Doggweiler, & Schmidt 1999) and a similar case might be
made for patients with PBS/IC, though scientific support for
a direct etiologic relationship is lacking.
PATHOLOGY
One can have pathology consistent with the diagnosis of IC,
but there is no microscopic picture pathognomonic of this
syndrome (Figs 10-7 and 10-8). The role of histopathology in
the diagnosis of IC is primarily one of excluding other possible diagnoses. One must rule out carcinoma and carcinomain-situ, eosinophilic cystitis, tuberculous cystitis, as well as any
other entities with a specific tissue diagnosis (Hellstrom,
Davis, & Shonnard 1979; Johansson & Fall 1990).
While earlier reports described a chronic, edematous pancystitis with mast cell infiltration, submucosal ulcerations and
involvement of the bladder wall and chronic lymphocytic
infiltrate (Smith & Dehner 1972; Jacobo, Stamler, & Culp
1974), these were cases culled from patients with severe disease and not representative of the majority of cases currently
diagnosed. The pathologic findings in IC are not consistent.
There has been a great variation in the reported histologic
Figure 10–7. Nonulcerative form of IC with dense lymphoid infiltrate in
the lamina propria. Hematoxylin and eosin (H&E), original magnification
X20. (Courtesy of John Tomaszewski, Hospital of the University of
Pennsylvania, Department of Pathology.)
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appearance of biopsies from IC patients, and even variation
among biopsies taken from the same patients over time
(Gillenwater & Wein 1988).
Lepinard and colleagues (Lepinard, Saint-Andre, & Rognon
1984) reported a pancystitis affecting the 3 layers of bladder
wall. In nonulcerative disease the vesical wall was never normal, epithelium being thinned and muscle being affected.
Johansson and Fall (Johansson & Fall 1990) looked at 64
patients with ulcerative disease and 44 with nonulcerative IC.
The former group had mucosal ulceration and hemorrhage,
granulation tissue, intense inflammatory infiltrate, elevated
mast cell counts and perineural infiltrates. The nonulcer
group, despite the same severe symptoms, had a relatively
unaltered mucosa with a sparse inflammatory response, the
main feature being multiple, small, mucosal ruptures and suburothelial hemorrhages that were noted in a high proportion
of patients. As these specimens were almost all taken immediately after hydrodistention, how much of the admittedly minimal findings in the nonulcer group were purely iatrogenic is
a matter of speculation. One can see completely normal biopsies in the nonulcerative IC group (Johansson & Fall 1994).
Transition from nonulcerative to ulcerative IC is a rare event
(Fall, Johansson, & Aldenborg 1987), and pathologically the
two types of IC may be completely separate entities. While
mast cells are more commonly seen in the detrusor in ulcerative IC (Holm-Bentzen, Jacobsen, Nerstrom, Lose, Kristensen,
Pedersen, Krarup, Feggetter, Bates, Barnard, &. 1987b), they
are also common in patients with idiopathic bladder instability (Moore et al. 1992). Mastocytosis in PBS/IC is best documented by tryptase immunocytochemical staining
(Theoharides, Kempuraj, & Sant 2001). Despite attempts to
develop a diagnostic algorithm based on the detrusor to
mucosa mast cell ratio and nerve fiber proliferation
(Hofmeister, He, Ratliff, Mahoney, & Becich 1997), mast cell
counts per se have no place in the differential diagnosis of this
clinical syndrome.
Lynes and coworkers (Lynes et al. 1990) concluded that
biopsy specimens are often not helpful in confirming the diagnosis. Although IC patients in his study had a higher incidence and degree of denuded epithelium, ulceration, and submucosal inflammation, none of these findings was pathogno-
monic. In addition, these “typical” findings occurred only in
IC patients with pyuria or small bladder capacity. Epithelial
and basement membrane thickness, submucosal edema, vascular ectasia, fibrosis, and detrusor muscle inflammation and
fibrosis were not significantly different in the IC and control
patients.
Attempts to definitively diagnose IC by electron
microscopy have also been very unsuccessful. Collan’s group
(Collan, Alfthan, Kivilaakso, & Oravisto 1976), in the first
such study, wrote that the similarity of the ultrastructure of
epithelial cells in controls and IC patients makes it improbable that the disease process originates in the epithelium. Other
investigators found no differences in the morphologic appearances of the glycocalyx and of urothelial cells in patients with
IC when compared with controls (Dixon, Holm-Bentzen,
Gilpin, Gosling, Bostofte, Hald, & Larsen 1986). Anderstrom
and colleagues (Anderstrom, Fall, & Johansson 1989) saw no
surface characteristics specific for IC, but believed that the
mucin layer covering the urothelial cells seemed reduced in IC
compared with controls, a fact disputed by in a very elegant
paper (Nickel, Emerson, & Cornish 1993). Elbadawi and Light
(Elbadawi & Light 1996) observed ultrastructural changes
sufficiently distinctive to be diagnostic in specimens submitted for pathologic confirmation of nonulcerative interstitial
cystitis. Marked edema of various tissue elements and cells
appeared to be a common denominator of many observed
changes. The wide-ranging discussion of the etiology of IC in
Elbadawi’shis papers is fascinating, but the pathological findings are potentially marred by the methodology, in that specimens were obtained after diagnostic hydrodistention
(Elbadawi 1997).
So what is the place of pathologic examination of tissue in
IC? Attempts to classify the painful bladder by the
pathoanatomical criteria described by Holm-Bentzen (HolmBentzen 1989) are of questionable value. There is a group of
patients with what she describes as “nonobstructive detrusor
myopathy” (Holm-Bentzen et al. 1985). In her series, these
patients with degenerative changes in the detrusor muscle
often had residual urine, a history of urinary retention, and an
absence of sensory urgency on cystometry with bladder
capacities over 400cc. Most would not be clinically confused
with IC. A similar English series (Christmas, Smith, & Rode
1996), however, included patients who met NIDDK research
criteria and associated detrusor myopathy with diminished
detrusor compliance and ultimate bladder contracture.
The Interstitial Cystitis Database (ICDB) study worked
backwards from symptoms to pathology, and concluded that
certain symptoms are predictive of specific pathologic findings (Tomaszewski, Landis, Brensinger, Hardy, & et.al. 1999;
Tomaszewski, Landis, Russack, Williams, Wang, Hardy,
Brensinger, Matthews, Abele, Kusek, & Nyberg 2001) (Table
10-5). Denson et. al. (Denson et al. 2000) analyzed forceps
biopsies from 65 females and 4 males with PBS/IC. Ten per
cent of specimens showed vasodilatation or submucosal
edema. Inflammation was absent in 30% of patients, and mild
in another 41%. Cystoscopic changes did not correlate with
degree of inflammation. Hanus and colleagues (Hanus et al.
2001) studied 84 biopsies from 112 PBS/IC patients and
reported a linear relationship between the mean bladder
capacity under anesthesia and severity of glomerulations.
They did not find a correlation between severity of symptoms
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Figure 10–8. Knifelike Hunner’s ulcer in IC. H&E, original magnification
X40. (Courtesy of John Tomaszewski, Hospital of the University of
Pennsylvania, Department of Pathology.)
21
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
Nighttime Frequency
Mast cell count in lamina propria on tryptase stain
Complete loss of urothelium
Granulation tissue in lamina propria
Vascular density in lamina propria
Urinary Urgency
Percentage of submucosal granulation tissue
Urinary Pain
Percentage of mucosa denuded of urothelium
Percentage of submucosal hemorrhage
From Tomaszewski JE, Landis JR: Baseline associations among pathologic
features and patient symptoms in the National Interstitial Cystitis Data
Base. J Urol 1999;161S:28.
and histopathological changes observed by light or electron
microscopy.
Rosamilia reviewed the pathology literature pertaining to
PBS/IC in 2 recent publications and presented her own data
(Rosamilia, Igawa, & Higashi 2003; Hanno, Baranowski, Fall,
Gajewski, Nordling, Nyberg, Ratner, Rosamilia, & Ueda 2005).
She compared forceps biopsies from 35 control and 34 PBS/IC
patients, 6 with bladder capacities less than 400cc under anesthesia. Epithelial denudation, submucosal edema, congestion
and ectasia and inflammatory infiltrate were increased in the
PBS/IC group. Submucosal hemorrhage did not differentiate
the groups, but denuded epithelium was unique to the IC
group and more common in those with severe disease. The
most remarkable finding in her study was that histological
parameters were normal and indistinguishable from control
subjects in 55% of IC subjects. Method of biopsy can be
important in interpreting findings, as transurethral resection
biopsies tend to show mucosal ruptures, submucosal hemorrhage and mild inflammation (Johansson & Fall 1990), while
histology is normal approximately half the time with cold-cup
forceps biopsies (; Mattila 1982; Lynes, Flynn, Shortliffe, &
Stamey 1990; Rosamilia, Igawa, & Higashi 2003).
KEY POINTS
been folded in to the rubric of the chronic pelvic pain syndrome, and can be difficult to distinguish from PBS/IC
(Hakenberg & Wirth 2002; Forrest & Schmidt 2004;). The
diagnosis of PBS/IC is by its very nature based upon the definition. In the past this was by default, the symptom criteria
enumerated by the NIDDK (Hanno, Landis, Matthews-Cook,
Kusek, & Nyberg, Jr. 1999b; Hanno, Landis, Matthews-Cook,
Kusek, & et.al. 1999a) (Table 10-1). It has now morphed largely into a diagnosis of chronic pain, pressure, or discomfort
associated with the bladder, usually accompanied by urinary
frequency in the absence of any identifiable cause (Hanno
2005; Hanno, Baranowski, Fall, Gajewski, Nordling, Nyberg,
Ratner, Rosamilia, & Ueda 2005). Diagnostic approaches vary
widely, and general agreement on a diagnostic algorithm
remains a future goal (Chai 2002; Nordling 2004; Nordling et
al. 2004). The disorder can be very difficult to diagnose until
symptoms become well established, unless one has a high level
of suspicion (Porru, Politano, Gerardini, Giliberto, Stancati,
Pasini, Tinelli, & Rovereto 2004). Frequency and pelvic pain of
long duration related to the bladder unrelated to other known
causes establishes a working diagnosis. It is often difficult for
patients to distinguish between sensations of pain, pressure,
discomfort, and urgency. Ask a patient why they void hourly,
and it is usually because of discomfort rather than convenience. Heavy reliance upon other aspects of the NIDDK
research criteria will result in under-diagnosing more than
half of patients (Hanno, Landis, Matthews-Cook, Kusek, &
Nyberg, Jr. 1999b). Interstitial cystitis symptom scales
(O'leary, Sant, Fowler, Jr., Whitmore, & Spolarich-Kroll 1997;
Goin, Olaleye, Peters, Steinert, Habicht, & Wynant 1998;
Moldwin & Kushner 2004), like the AUA symptom score for
BPH, are designed to evaluate the severity of symptomatology
and monitor disease progression or regression with or without treatment. They have not been validated as diagnostic criteria.
One must rule out infection and less common conditions
including but not limited to carcinoma (Utz & Zincke 1974;
Tissot, Diokno, & Peters 2004), eosinophilic cystitis
(Hellstrom, Davis, & Shonnard 1979; Sidh et al. 1980;
Littleton, Farah, & Cerny 1982; Aubert, Dore, & Touchard
1983; Abramov et al. 2004), malakoplakia, schistosomiasis,
scleroderma (Batra & Hanno 1997), and detrusor endometriosis (Sircus, Sant, & Ucci, Jr. 1988; Price et al. 1996). In
men under the age of 50, videourodynamics are useful to ruleout voiding dysfunction resulting from vesical neck obstruction, “pseudo” dyssynergia, or impaired contractility (Kaplan
et al. 1996). Musculoskeletal dysfunction may also play a role
in causation or increasing symptom severity and should be
looked for in the diagnostic phase of evaluation (Prendergast
& Weiss 2003). Reports of successful treatment of IC symptoms by laparoscopic adhesiolysis (Chen, Lin, & Gardner
1997) or urethral diverticulum excision (Daneshgari, Zimmern, & Jacomides 1999) give credence to the fact that IC is a
diagnosis of exclusion. Many drugs including cyclophosphamide, aspirin, nonsteroidal anti-inflammatory agents, and
allopurinol have caused a nonbacterial cystitis that resolves
with drug withdrawal (Bramble & Morley 1997; Gheyi,
Robertson, & Atkinson 1999).
Various gynecologic problems can mimic the pain of IC
(Kohli, Sze, & Karram 1997). The pelvic congestion syndrome,
a condition of the reproductive years and equally prevalent
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Table 10-5. Associations Among Pathologic Features
and Patient Symptoms
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Histopathology plays a supportive diagnostic role at
most (Johansson, Ogawa, & Fall 1997). While recent
studies suggest that a severely abnormal pathology
may be associated with poor prognosis (Mcdougald M
2003; Nordling et al. 2003), this is not necessarily the
case (MacDermott et al. 1991a). Interstitial cystitis is a
diagnosis of exclusion, and, at this point in time,
excluding other diseases that are pathologically identifiable is the primary utility of bladder biopsy in this
group of patients.
DIAGNOSIS
PBS/IC can be considered one of the chronic visceral pain
syndromes, affecting the urogenital and rectal area, many of
which are well-described but poorly understood (Wesselmann, Burnett, & Heinberg 1997; Wesselmann 2001;).
These include vulvodynia, orchialgia, penile pain, perineal
pain, and rectal pain. In men, many of the entities have now
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Bouchelouche, Cervigni, Elneil, Fall, Hald, Hanus, Hedlund,
Hohlbrugger, Horn, Larsen, Leppilahti, Mortensen, Nagendra,
Oliveira, Osborne, Riedl, Sairanen, Tinzl, & Wyndaele 2004;
Hanno 2005; Hanno, Baranowski, Fall, Gajewski, Nordling,
Nyberg, Ratner, Rosamilia, & Ueda 2005).
Although sensations reported during cystometric bladder
filling are subjective, they have a normal pattern and may be
helpful in distinguishing bladder pathology (Wyndaele 1998).
Many dispute the need for urodynamic study, but we agree
with Siroky that not only can it help to assess bladder compliance and sensation and reproduce the patient's symptoms
during bladder filling, but it can help to rule out detrusor
overactivity (DO) (Siroky 1994). Women with pain on filling
can be indistinguishable from those with DO in their perception of bladder fullness (Creighton et al. 1991). One should be
wary of diagnosing IC in patients with discrete, involuntary
bladder contractions whose symptoms respond to anticholinergic therapy. The two problems coexist in 15-19% of patients
(Gajewski & Awad 1997; Kirkemo et al. 1997), but the pathophysiology is likely to be very different. Patients who respond
to anticholinergic medication tend not to respond to standard
therapy for interstitial cystitis (Perez-Marrero, Emerson, &
Juma 1987). If involuntary contractions are noted and the
patient’s symptoms of frequency and pain continue despite
successful treatment, one is on firmer ground in considering a
diagnosis of IC. Complex cases may benefit from full
videourodynamics studies (Carlson, Rome, & Nitti 2001).
Cystometry in conscious IC patients generally demonstrates normal function, the exception being decreased bladder capacity and hypersensitivity. Pain on bladder filling
which reproduces the patient’s symptoms is very suggestive of
IC. Bladder compliance in patients with IC is normal, as
hypersensitivity would prevent the bladder from filling to the
point of noncompliance (Siroky 1994; Rovner & Wein 1999).
The possible addition of including a second cystometrogram
following instillation of intravesical lidocaine to help to determine if pain is bladder-related is a provocative one worth further study (Teichman, Nielsen-Omeis, & McIver 1997).
Long before it was considered a diagnostic tool, cystoscopy
with hydrodistention of the bladder (CHD) was used as a
therapeutic modality for IC (Bumpus 1930) (Bumpus 1930).
CHD under anesthesia allows for sufficient distention of the
bladder to afford visualization of either glomerulations or
Hunner's ulcers (Figs 10-9 and 10-10). After filling to 80cm
water pressure for one to two minutes, the bladder is drained
and refilled. The terminal portion of the effluent is often
blood-tinged. Reinspection will reveal the pin-point petechial
hemorrhages that develop throughout the bladder after distention and are not usually seen after examination without
anesthesia (Nigro & Wein 1997).
Glomerulations are not specific for IC (Erickson 1995;
Waxman, Sulak, & Kuehl 1998), and only when seen in conjunction with the clinical criteria of pain and frequency can
the finding of glomerulations be viewed as significant.
Glomerulations can be seen after radiation therapy, in
patients with carcinoma, after exposure to toxic chemicals or
chemotherapeutic agents, and often in patients on dialysis or
after urinary diversion when the bladder has not filled for prolonged periods. They have been reported in the majority of
men with prostate pain syndromes, begging the question as to
whether the chronic pelvic pain syndrome in men is closely
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among parous and nulliparous women, is manifest by shifting
location of pain, deep dyspareunia and postcoital pain, and
exacerbation of pain after prolonged standing (Stones 2003).
Similar symptoms can be seen in PBS/IC. Other gynecologic
disorders can include pelvic tumors, vaginal atrophy, vulvodynia, vestibulitis, pelvic relaxation, pelvic adhesive disease, levator ani myalgia, and undiagnosed chronic pelvic pain (Myers
& Aguilar 2002). Endometriosis probably causes pain, but that
conclusion has to be regarded carefully, as it is based largely on
one study (Sutton et al. 1997). Whiteside and Falcone
(Whiteside & Falcone 2003) point out that any claim linking
endometriosis with pain fails to account for the common
experience that identical lesions can be found in symptomatic
and asymptomatic women (Vercellini 1997). Between 2% and
43% of asymptomatic women are found to have endometriosis (Moen & Stokstad 2002). Furthermore, there does not
appear to be any risk for patients with asymptomatic mild
endometriosis to develop symptoms even after greater than 10
years (Moen & Stokstad 2002). While 70% to 90% of women
with chronic pelvic pain have endometriosis, this does not
definitively establish causation (Gambone et al. 2002).
Laparoscopy, which is not considered essential before initiating hormonal treatment of endometriosis (Howard 2003b),
should not be considered a part of any routine evaluation of
PBS/IC unless a gynecologist believes it is likely to benefit the
patient.
A presumptive diagnosis can be made merely by ruling out,
known causes of frequency and pain/urgency in a patient with
compatible chronic symptoms. Often this will involve a complete history, physical examination, appropriate cultures, and
local cystoscopy. In the absence of microhematuria, the value
of cytology is questionable (Duldulao, Diokno, & Mitchell
nsider important, especially if
1997), but something we still consider
bladder carcinoma in situ is a serious possibility, as in patients
over 40 and those with a smoking history. The recent report of
a large series of PBS/IC patients indicating that 1% actually
had transitional cell carcinoma, and that 4 of the 6 cancer
patients did not have microhematuria, provides evidence for
the justification of local cystoscopic examination (Tissot,
Diokno, & Peters 2004).
It must be recognized that one may sacrifice a certain level
of confidence in the diagnosis without the supporting evidence that can be furnished by additional studies. In a longterm illness like IC, many patients and physicians ultimately
want to base a diagnosis and treatment plan on the most complete data set possible (Rovner & Wein 1999). A more thorough evaluation for IC would also include a urodynamic evaluation and cystoscopy under anesthesia with hydrodistention
of the bladder (Hanno, Levin, Monson, Teuscher, Zhou,
Ruggieri, Whitmore, & Wein 1990; Hanno 1994a). Bladder
biopsy is indicated only if necessary to rule out other disorders that might be suggested by the cystoscopic appearance.
Cystoscopy under anesthesia with bladder distention has been
important in the identification of a Hunner’s ulcer.
Experimental data suggests that measurement of increased
nitric oxide levels in the bladder can also accurately identify
those with ulcerative disease (Logadottir et al. 2004). The
diagnosis is generally subject to more rigorous testing in
Europe than in North America, where symptoms in the
absence of other obvious causes seems to be the gold standard
(Nordling 2004; Nordling, Anjum, Bade, Bouchelouche,
23
CHAPTER 10
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Physiology, Pathology, and Management of Upper Urinary Tract Diseases
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Figure 10–9. Typical appearance of
glomerulations after bladder distention
in a patient with nonulcerative IC.
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linked with interstitial cystitis (Berger et al. 1998). We have
speculated that they may simply reflect the response of the
bladder to distention after a prolonged period of chronic
underfilling because of sensory urgency, rather than result
from a primary pathologic process. While the presence of a
Hunner’s ulcer has been associated with pain and urinary
urgency, neither the findings of bloody irrigating fluid nor
glomerulations are strongly associated with any particular
symptom in patients in the Interstitial Cystitis Database
(Messing et al. 1997).
Further confusion arises when the patient demonstrates the
symptoms of interstitial cystitis but the cystoscopic findings
under anesthesia are completely normal. This occurred in
8.7% of patients undergoing CHD entered into the IC database (Messing, Pauk, Schaeffer, Nieweglowski, Nyberg, Jr.,
Landis, Cook, & Simon 1997). Awad and colleagues recog-
Figure 10–10. Typical appearance of Hunner’s ulcer in an IC patient before
bladder distention.
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The Search for a Marker
mination by tryptase staining (Erickson, Kunselman, Bentley,
Peters, Rovner, Demers, & Tomaszewski 2004).
Attempts have been made to look at other markers
(Erickson 2001) including eosinophil cationic protein (Lose et
al. 1987), glycosaminoglycan excretion (Hurst et al. 1993), and
urinary histamine and methylhistamine (El Mansoury,
Boucher, Sant, & Theoharides 1994). Proposals for measuring
smooth muscle isoactin expression (Rivas, Chancellor, ShuppByrne, Shenot, McHugh, & McCue 1997) and urinary levels of
neurotrophin-3, nerve growth factor, glial cell line-derived
neurotrophic factor, and tryptase (Okragly, Niles, Saban,
Schmidt, Hoffman, Warner, Moon, Uehling, & HaakFrendscho 1999) have been suggested. Low levels of GP51, a
urinary glycoprotein with a molecular weight of 5`kDa have
been documented in IC patients compared to normal controls
and patients with other urinary tract diseases (Byrne et al.
1999). Even cell cultures (Elgavish et al. 1997) and the measurement of elevated nitric oxide levels in air instilled and
incubated in the bladder have been proposed for office screening (Ehren et al. 1999; Lundberg et al. 1996).
The urine antiproliferative factor (APF) identified by Keay
(see above) may prove to be the most accurate marker of
PBS/IC when confirmed by other centers. It appears to have
the highest sensitivity and specificity of the variety of possible
markers tested, and fits nicely into an etiologic schema (Keay,
Zhang, Shoenfelt, Erickson, Whitmore, Warren, Marvel, &
Chai 2001; Erickson, Xie, Bhavanandan, Wheeler, Hurst,
Demers, Kushner, & Keay 2002). It has also been shown to differentiate men with PBS/IC symptoms from controls, and differentiate men with bladder associated pain and irritative
voiding symptoms from those with pelvic/perineal pain alone
and other nonspecific findings compatible with the chronic
pelvic pain syndrome in men (CPPS III), previously referred
to as “nonbacterial prostatitis” (Keay, Zhang, Chai, Warren,
Koch, Grkovic, Colville, & Alexander 2004a). This evidence
that CPPS and PBS/IC are very likely two different disorders
will doubtless be the subject of future research.
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nized this entity soon after the NIDDK research criteria had
been described. They reported on a series of patients in whom
the symptomatology, urodynamic evaluation, histology, and
response to therapy was identical to IC, in whom findings on
CHD were normal. It was termed “idiopathic reduced bladder
storage” (Awad, MacDiarmid, Gajewski, & Gupta 1992).
Clinical, urodynamic, and cystoscopic data strongly suggest
that the presence of glomerulations is not selecting out a
meaningful difference in patients with symptoms of PBS/IC
(Al Hadithi, Tincello, Vince, & Richmond 2002). The presence
of glomerulations on cystoscopy under anesthesia meeting the
NIDDK criteria may identify a group of patients with worse
daytime frequency and nocturia, and lower bladder capacity
under anesthesia, but does not have any relationship to biopsy findings, bladder pain, or urgency (Erickson et al. 2005).
Ultimately, disease definitions are helpful only relative to the
utility they provide in terms of treatment and prognosis, and
it is likely that the definition of interstitial cystitis and therefore proper methods of diagnosis will continue to evolve.
What is the value of a “diagnostic test” in what is essentially a
clinical syndrome defined by a symptom complex? If a patient
has chronic pain associated with the bladder usually accompanied by urinary frequency with no discernible cause, we
diagnose PBS/IC. In essence, once we have ruled out wellcharacterized pathologic entities, the patient makes the diagnosis by relating symptoms; much like a patient with impotence makes that diagnosis. Testing for impotence may give
clues as to etiology, but we cannot rule out impotence in a
patient who can’t function sexually by doing a test!
This is not to say that establishment of a valid diagnostic
marker would not be a major advance in our understanding
of IC. It will be important largely to the extent that it can predict prognosis in a given group of patients, predict response to
therapy in a given group of patients, and/or distinguish
between IC and another possible cause of the symptom complex that has been diagnosed. Ultimately marker identification may enable us to stratify patients with the symptom complex in such a way that treatments will be specific to the specific etiology (disease) the patient has. As various etiologies
are identifiable, the diagnosis of interstitial cystitis may itself
become a rarity, much as what has happened to “acute urethral syndrome” (Stamm et al. 1980).
In just such an effort, numerous investigators have looked
at the mast cell as a possible diagnostic marker for interstitial
cystitis. The results have been very contradictory, and at this
time, in terms of the use of mast cell criteria in diagnosis, the
issue remains moot (Kastrup, Hald, Larsen, & Nielsen 1983;
Lynes, Flynn, Shortliffe, Lemmers, Zipser, Roberts, & Stamey
1987; Feltis, Perez-Marrero, & Emerson 1987; Holm-Bentzen,
Sondergaard, & Hald 1987; Hanno, Levin, Monson, Teuscher,
Zhou, Ruggieri, Whitmore, & Wein 1990; Christmas & Rode
1991; Moore, Nickson, Richmond, Sutherst, Manasse, &
Helliwell 1992; Dundore, Schwartz, & Semerjian 1996;
Hofmeister, He, Ratliff, Mahoney, & Becich 1997). Methylhistamine, a histamine metabolite found in the urine and
thought to reflect mast cell activation, was not associated with
symptom scores, response to bladder distention, cystoscopic
findings, or bladder biopsy features including mast cell deter-
25
Potassium Chloride Test
Parsons has championed an intravesical potassium chloride
challenge, comparing the sensory nerve provocative ability of
sodium versus potassium using a 0.4 M potassium chloride
solution. Pain and provocation of symptoms constitutes a
positive test. Whether the results indicate abnormal epithelial
permeability in the subgroup of positive patients, or hypersensitivity of the sensory nerves is unclear. Normal bladder
epithelium can never be absolutely tight, and there is always
some leak, however small (Hohlbrugger 1997). The concentration of potassium used is 400meq per liter, far exceeding
the physiologic urinary concentrations of 20-80meq/liter
depending upon dietary intake (Vander 1995). Healthy controls can distinguish KCl from sodium chloride, though they
don’t experience severe pain (Roberto et al. 1997). The hope is
that this test may stratify patients into those who will respond
to certain treatments (perhaps those designed to fortify the
glycosaminoglycan layer), but to date this information is lacking (Teichman & Nielsen-Omeis 1999).
Used as a diagnostic test for interstitial cystitis, the potassium chloride test is not valid (Chambers et al. 1999). The gold
standard in defining PBS/IC for research purposes has been
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
Table 10-6. University of Wisconsin Symptom
Instrument (J. Urol. 173:835-840, 2005)
Symptom
Score 1-6 (0=not at all) (6=a lot)
1. Bladder discomfort
2. Bladder pain
3. Other pelvic discomfort
4. Headache
5. Backache
6. Dizziness
7. Feelings of suffocation
8. Chest pain
9. Ringing in ears
10. Getting up at night to go to the bathroom
11. Aches in joints
12. Swollen ankles
13. Nasal congestion
14. Flu
15. Abdominal cramps
16. Numbness or tingling in fingers or toes
17. Nausea
18. Going to the bathroom frequently during the day
19. Blind spots or blurred vision
20. Heart pounding
21. Difficulty sleeping because of bladder symptoms
22. Sore throat
23. Urgency to urinate
24. Coughing
25. Burning sensation in bladder
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the NIDDK criteria. These criteria are recognized to constitute
a set of patients that virtually all researchers can agree have
PBS/IC, though they are far too restrictive to be used in clinical practice (Hanno, Landis, Matthews-Cook, Kusek, &
Nyberg, Jr. 1999b). Thus, this group of patients should virtually all be positive if the KCl test is to have the sensitivity needed to aid in diagnosis. Up to 25% of patients meeting the
NIDDK criteria will have a negative KCl test (Parsons,
Greenberger, Gabal, Bidair, & Barme 1998). In the group it
should perform the best in, it is lacking in sensitivity. When we
look at the specificity side of the equation, in the universe of
asymptomatic persons, it performs relatively well and is rarely
positive, although a recent study reported a 36% false positive
rate in asymptomatic men (Yilmaz et al. 2004). It is in the
patient population with confounding conditions for which we
would want help in sorting out PBS/IC from other disorders.
Twenty-five percent of patients with overactive bladder test
positive and virtually all patients with irritative symptoms
from radiation cystitis and urinary tract infection test positive
(Parsons, Stein, Bidair, & et.al. 1994b; Parsons, Greenberger,
Gabal, Bidair, & Barme 1998). The results with chronic prostatitis / chronic pelvic pain syndrome in men are variable, but
50-84% of men have been reported to test positive (Parsons &
Albo 2002; Yilmaz, Liu, Rothman, Lee, Yang, & Berger 2004;
Parsons et al. 2005). In women with pelvic pain results are
similar (Parsons, Dell, Stanford, Bullen, Kahn, & Willems
2002b), and based on these findings, Parsons has expressed
the view that PBS/IC may affect over 20% of the female population of the United States (Parsons et al. 2002a). Another
way to interpret the findings would be that the KCl test is very
nonspecific, missing a significant number of PBS/IC patients
and over-diagnosing much of the population.
Cystometry employing potassium chloride (0.3M) has been
compared to saline cystometry in patients with PBS/IC and
those with detrusor overactivity (Philip & Irwin 2004). Both
groups show lowered volumes at first desire to void and lower
cystometric capacity with KCl, raising the question as to
whether potassium may act not on the urothelial sensory
mechanism, but rather on the detrusor muscle.
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 (Chambers, Fenster, Cripps, Jens, &
Taylor 1999; Gregoire et al. 2002; Kuo 2003). The development
of a painless modification of the potassium chloride test
(Daha et al. 2003) using cystometric capacity and a .2M solution may improve acceptability among patients, but further
research is needed to determine what place, if any, this test will
have in the diagnostic or treatment algorithm for PBS/IC.
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CLINICAL SYMPTOM SCALES
Symptom scales have potential utility in PBS/IC. Their future
development may enable reliable diagnosis of the syndrome
on the basis of a questionnaire alone. A brief survey that reliably segregates PBS/IC from other urologic disorders would
make the ability to diagnose the syndrome reliable, inexpensive, and available to all healthcare providers. It would aid in
epidemiologic studies as well. Currently such work sponsored
by NIDDK is ongoing (http://kidney.niddk.nih.gov/about/
Research_Updates/spr04/6.htm). Questionnaires and symptom scales can also be utilized to measure treatment outcome
and are especially valuable in clinical research studies as well
as for guiding therapy for individual patients.
There are 3 published PBS/IC symptom questionnaires: the
University of Wisconsin IC Scale, the O’Leary-Sant IC
Symptom Index and IC Problem Index, and the Pelvic Pain
and Urgency/Frequency (PUF) Scale.
The University of Wisconsin IC Scale (Table 10-6) includes
7 PBS/IC symptom items (1,2,10,18,21,23, and 25), but has
not been validated for identification or diagnosis of PBS/IC. It
captures severity of symptom expression (Keller, McCarthy, &
Neider 1994; Goin, Olaleye, Peters, Steinert, Habicht, &
Wynant 1998). PBS/IC patients do not appear to indiscriminately report higher scores than controls for different somatic
and general complaints (Porru et al. 2005). Unlike the other
two instruments, it addresses some quality-of-life issues, and
this is an advantage when such issues are subject of investigation. Its most attractive aspects are its clinically apparent face
validity and its ease of implementation.
The O’Leary-Sant indiceexes (Table 10-7) formare a validated questionnaire that was originally developed by focus
groups, subjected to test-retest reliability analysis, and validated by administration to IC patients and asymptomatic controls (O'leary, Sant, Fowler, Jr., Whitmore, & Spolarich-Kroll
1997; Lubeck et al. 2001). The questionnaires centers on 3
questions related to urgency/frequency and one on bladderassociated pain. TheyIt does not address generalized pelvic
pain or symptomatology associated with sexual activity. This
is not because these questions were not considered in the formulation of the questionnaire. Of 73 questions in the preliminary instrument covering domains of urinary symptoms,
pain, sexual function, menstrual variability, and general
Table 10-7.
27
This is a Table Title
IC Problem Index
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IC Symptom Index
From O’leary MP, Sant GR, et.al, The interstitial cystitis symptom index and problem index, Urology, 49:5A (S), 58-63, 1997
health, only the four questions now in the instrument were
needed to reliably and validly describe the illness experience
of those with IC and distinguish these patients from those
without the disorder (O'leary & Sant 1997).
The most recently published instrument is the PUF questionnaire (Parsons, Dell, Stanford, Bullen, Kahn, Waxell, &
Koziol 2002a) (Table 10-8). It was specifically designed to
include questions that directly reflect a wide variety of the
symptoms experienced by patients who are affected by this
disorder. One-third of the questions address pelvic pain,
including pain anywhere in the pelvis: the vagina, labia, lower
abdomen, urethra, perineum, testes, penis, or scrotum. A large
study utilizing the PUF questionnaire has concluded that up
to 23% of American females have PBS/IC (Parsons, Dell,
Stanford, Bullen, Kahn, Waxell, & Koziol 2002a). This makes
one very wary as to the utility and face-validity of the PUF (Ito
et al. 2003). A total score of 10-14 =74% likelihood of positive
potassium test (PST); 15-19=76%; 20+=91%. To the extent
that the PST is suspect, the reliability of PUF data comes into
question.
None of the questionnaires has been shown to be of value
in diagnosis (Moldwin & Kushner 2004). The O’Leary-Sant
and University of Wisconsin instrument correlate strongly in
a large population of patients with PBS/IC (Sirinian & Payne
2001). Treatment outcome studies have also used the Global
Response Assessment; a balanced patient self-report on overall response to therapy, developed for NIDDK sponsored multicenter therapeutic trials (Sant et al. 2003) (Table 10-9).
KEY POINTS
Symptom scales have potential utility in PBS/IC. Their
future development may enable reliable diagnosis of
the syndrome on the basis of a questionnaire alone. A
brief survey that reliably segregates PBS/IC from other
urologic disorders would make the ability to diagnose
the syndrome reliable, inexpensive, and available to all
healthcare providers. It would aid in epidemiologic
studies as well. Currently such work sponsored by
NIDDK is ongoing (http://kidney.niddk.nih.gov/
about/Research_Updates/spr04/6.htm). Questionnaires and symptom scales can also be utilized to
measure treatment outcome and are especially valuable in clinical research studies as well as for guiding
therapy for individual patients. None of the questionnaires has been shown to be of value in diagnosis
(Moldwin & Kushner 2004).
ASSESSING TREATMENT RESULTS
The diversity of PBS/IC therapies underscores the lack of
understanding about the treatment of this syndrome (Rovner
et al. 2000). It has been not only a difficult condition to diagnose, but also a difficult condition for which to assess therapeutic impact. There is a 50% incidence of temporary remission unrelated to therapy, with a mean duration of 8 months
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF)
Table 10-9.
Global Response Assessment (GRA)
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Table 10-8.
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-3: Markedly worse
-2: Moderately worse
-1: Slightly worse
0: No change
+1: Slightly improved
+2: Moderately improved
+3: Markedly improved
(Held, Hanno, & Wein 1990). A somewhat surprising finding
from the Interstitial Cystitis Database was that although there
was initial improvement in symptoms partially due to regression to the mean (Sech et al. 1998) and the intervention effect,
there was no evidence of a long-term change in average symptom severity over the four year course of follow-up (Propert,
Schaeffer, Brensinger, Kusek, Nyberg, & Landis 2000). 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 (Fig
10-11). They are often victims of unorthodox health care
providers with untested forms of therapy, some medical, some
homeopathic, and some even surgical.
Placebo effects influence patient outcomes after any treatment, including surgery, which the clinician and patients
believe is effective. Placebo effects plus disease natural history
and regression to the mean can result in high rates of good
29
outcomes, which may be misattributed to specific treatment
effects (Gillespie et al. 1991; Gillespie 1994; Turner et al. 1994;
Propert, Schaeffer, Brensinger, Kusek, Nyberg, & Landis 2000).
Unfortunately, few IC treatments have been subjected to a
placebo-controlled trial. This is not to say that what seems
effective is not, but rather that a high index of skepticism is
healthy, even in treatments tested by controlled trials (Schulz
et al. 1995). While in many diseases an argument can be made
against using a true placebo control as opposed to an orthoORAL THERAPIES
100
80
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60
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40
20
0
Cimetidine
Nifedipine
Cyclosporin
PPS
L-Arginine
Hydroxyzine Amitriptyline
INTRAVESICAL TREATMENTS
80
Figure 10–11. Selected reported
treatment outcomes in uncontrolled
studies in IC literature: Percentage of
patients initially improved. Ag nitrate,
silver nitrate; BCG, bacillus CalmetteGuérin; DMSO, dimethyl sulfoxide; PPS,
sodium pentosanpolysulfate; TENS, transcutaneous electrical nerve stimulation.
60
40
20
0
DMSO
Heparin
Clorpactin
Ag nitrate
BCG
Hyaluronic
acid
OTHER TREATMENT OPTIONS
90
80
70
60
50
40
30
20
10
0
Acupuncture
TENS
Spontaneous
remission
Ulcer
resection
Cystoplasty Cystectomy
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
ful waiting”. If the patient has not had an empiric course of
antibiotics for their symptoms by the time the PBS/IC diagnosis is made, such a trial is reasonable. Doxycycline has been
reported efficacious in a recent Swiss study (Burkhard, Blick,
Hochreiter, & Studer 2004). Further attempts to alleviate
symptoms with antibiotics are unlikely to be worthwhile and
are not recommended in the absence of positive cultures
(Warren, Horne, Hebel, Marvel, Keay, & Chai 2000. If the
patient's symptoms are livable, the withholding of immediate
treatment is reasonable. While the concept of “livable” is certainly patient dependent, someone who gets up once or twice
a night and voids every 2-3 hours during the day with minimal pain would certainly fall into this category. An educated
patient is likely to realize that no treatment will make them
perfect, and any therapy is a tradeoff among the inconvenience, chronicity of treatment, side effects, and the benefits.
As with any decision in medicine, “perfect is the enemy of
good”. Data that “early” treatment affects the natural history
or course of the disease is lacking at this time, and an argument for the early institution of therapy cannot be supported
on the basis of epidemiologic data or clinical trials.
Patient education and empowerment is an important initial
step in therapy. Taking advantage of on-line data bases, interactive computer programs, electronic mail lists for disabled
persons, telephone hotlines, educational videos, health magazines, and public libraries enables patients to make health
choices that they can feel comfortable with (McCormick 1997;
Breau, McGrath, & Norman 2003). It is important to reassure
the patient (who often has already seen multiple doctors and
had many tests) that the symptoms, although very bothersome, are not signs of a life-threatening disease. Patients are
usually reassured learning that they are not the only persons
with these symptoms, and that what they have is a part of a
well-described syndrome. One must not forget the placebo
effect, euphemistically termed “remembered wellness”, as one
of the physician’s most therapeutic assets (Benson & Epstein
1976; Benson & Friedman 1996; O'Reilly et al. 2004). The
Interstitial Cystitis Association (Ratner, Slade, & Whitmore
1992) is an important resource for information and support
for patients as well as a clearing house for ideas and funding
for researchers and clinicians.
There is data that timed voiding and behavioral modification therapy can be helpful in the short-term, especially in
patients where frequency rather than pain predominates
(Chaiken, Blaivas, & Blaivas 1993; Barbalias et al. 2000). This
can consist of diary keeping, controlled fluid intake, pelvic
floor muscle training, and active attempts to increase voiding
intervals. Parson’s group reported success in 15 of 21 patients
who had primarily frequency rather than pain, by gradually
encouraging longer voiding intervals over time through voiding diary techniques (Parsons & Koprowski 1991). A similar
study with 15 patients concluded that although average voided volume increased by 65cc after a month, the persistent
sense of bladder fullness did not change from pre-intervention volumes (Mendelowitz & Moldwin 1997).
While there are no randomized, controlled trials to prove it,
many clinicians believe that stress reduction, exercise, warm
tub baths, and efforts by the patient to maintain a normal
lifestyle all contribute to overall quality of life (Whitmore
1994). In a controlled study of 45 PBS/IC patients and 31
healthy controls, higher levels of stress were related to greater
pain and urgency in patients with IC, but not in the control
AL
dox treatment of approved or accepted value (Rothman &
Michels 1994), a good case for true placebo can readily be
made for interstitial cystitis. The vagaries of the natural history, the general lack of progression of symptom severity over
time, and the fact that it is not life threatening, mean that
there is little to lose and much to gain by subjecting new treatments to the vigorous scrutiny of placebo control. Many
patients who volunteer for such trials have already run the
gamut of accepted (though generally unproved) therapies. It
has long been recognized in protocols that use subjective criteria for assessment that “improvement” may be expected in
up to 35% of placebo-treated patients (Benson & Epstein
1976). As the spontaneous remission rate (though temporary)
for IC is 11% (Oravisto & Alfthan 1976) to 50% (Held,
Hanno, & Wein 1990), combined with the placebo improvement it can be difficult to prove efficacy. Even in placebo controlled trials, it is reasonable to surmise that some degree of
unblinding may occur as a result of somatic or psychological
side effects of the active arm, impairing the validity of the trial
results and giving the active arm a slight edge over placebo
(DuBeau, Khullar, & Versi 2005; Rees et al. 2005). This is of
specific concern in PBS/IC and any disorder where primary
outcomes may be subject to patient-specific psychological and
physiological factors.
The value of placebo-controlled trials is aptly illustrated by
the recent decisions by pharmaceutical manufacturers not to
pursue FDA approval in the United States for seemingly
promising intravesical therapies for PBS/IC (Morales et al.
1996; Chancellor & de Groat 1999) after placebo-controlled
trials failed to establish efficacy. These include low concentration hyaluronic acid (Bioniche, Canada), high concentration
hyaluronic acid (SKK, Tokyo), and resiniferatoxin (ICOS,
Bothell, Washington, USA). Nalmefene, an initially promising
oral therapy in the 1990’s (Stone 1994), also failed phase 3 trials (IVAX, Miami). Placebo trials are impractical in surgery
and it can be difficult to evaluate surgical reports. The many
older medications currently used off-label might not meet
success if tested in the stringent manner in which new molecular entities are tested. The expense of testing therapies currently used off-label often requires dependence on the largesse
of government agencies like the National Institute of Health
(Propert et al. 2002; Sant, Propert, Hanno, Burks, Culkin,
Diokno, Hardy, Landis, Mayer, Madigan, Messing, Peters,
Theoharides, Warren, Wein, Steers, Kusek, & Nyberg 2003;
Mayer & Interstial cystitis clinical trials group 2005).
Finally, when considering objective changes, the concept of
statistical versus clinical significance is paramount.
Investigators should, but rarely do, point out differences
between statistical improvement and what they consider to be
clinically significant improvement (Wein & Broderick 1994).
As Gertrude Stein reportedly stated, “A difference, to be a difference, must make a difference”. An increase in bladder
capacity of 30cc may be statistically significant but clinically
irrelevant. Number needed to treat and number needed to
harm data (McQuay H 2003) may be particularly important
in PBS/IC and have not typically been included in efficacy
analysis.
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CONSERVATIVE THERAPY
Once the diagnosis has been made one must decide whether
to institute therapy or employ a policy of conservative “watch-
Table10-10.
Fruits
Apples
Apricots
Avocados
Bananas
Cantaloupes
Citrus fruits
Cranberries
Grapes
Nectarines
Peaches
Pineapples
ORAL THERAPY (Table 10-11)
Tricyclic Antidepressants
AL
Amitriptyline has become a staple of oral treatment for interstitial cystitis. The tricyclics possess varying degrees of at least
three major pharmacologic actions: 1) they have central and
peripheral anticholinergic actions at some but not all sites, 2)
they block the active transport system in the presynaptic nerve
ending that is responsible for the re-uptake of the released
amine neurotransmitters serotonin and noradrenaline, and 3)
they are sedatives, an action that occurs presumably on a central basis but perhaps is related to their antihistaminic properties. Amitriptyline, in fact, is one of the most potent tricyclic
antidepressants in terms of blocking H1-histaminergic receptors (Baldessarini 1985). There is also evidence that they
desensitize alpha2 receptors on central noradrenergic neurons. Paradoxically, they also have been shown to block alphaadrenergic receptors and serotonin receptors. Theoretically,
tricyclic agents have actions that might tend to stimulate predominantly beta-adrenergic receptors in bladder body
smooth musculature, an action that would further facilitate
urine storage by decreasing the excitability of smooth muscle
in that area (Barrett & Wein 1987).
Interstitial Cystitis Association Recommendations of Foods to Avoid WWW.ICHELP.ORG
Milk/Dairy Products
Aged cheeses
Sour cream
Yogurt
Chocolate
Vegetables
Fava beans
Lima beans
Onions
Tofu
Soybeans
Tomatoes
pH (7.5). There was no statistically significant difference in
subjective pain scores, suggesting that adjusting urine pH with
diet or dietary supplements may have little influence on
symptomatology. Orange and grapefruit juices, rich in potassium and citrate, tend to increase urinary pH (Wabner & Pak
1993), but surprisingly are avoided by many IC patients based
on “IC diet” recommendations. Urinary alkalinization may be
worth trying, but supporting studies are lacking.
Unfortunately education and self-help are often not sufficient, and most patients will require one or more of a variety
of therapies.
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group (Rothrock et al. 2001). Maladaptive strategies for coping with stress may impact adversely on symptoms (Rothrock,
Lutgendorf, & Kreder 2003). Biofeedback, soft tissue massage,
and other physical therapies may aid in muscle relaxation of
the pelvic floor (Mendelowitz & Moldwin 1997; Meadows
1999; Holzberg, Kellog-Spadt, Lukban, & Whitmore 2001;
Lukban et al. 2001; Markwell 2001). Mendelowitz and
Moldwin (Mendelowitz & Moldwin 1997) had a 69% success
rate in 16 patients treated with electromyographic biofeedback, but treatment response did not correlate to changes in
muscle identification, and the placebo effect may have been
considerable. Acupuncture has been used for PBS/IC and
many other chronic pain syndromes. There is limited evidence
that it is more effective than non treatment for chronic pain,
and inconclusive evidence that acupuncture is more effective
than placebo, sham acupuncture, or standard care (Ezzo et al.
2000). PBS/IC results with acupuncture have been disappointing (Geirsson et al. 1993).
Elaborate dietary restrictions are unsupported by any literature, but many patients do find their symptoms are adversely affected by specific foods and would do well to avoid them
(Koziol, Clark, Gittes, & Tan 1993; Koziol 1994). Often this
includes caffeine, alcohol, and beverages that might acidify the
urine like cranberry juice. Anecdotal association of interstitial
cystitis with many foods has spawned the recommendation of
various “interstitial cystitis diets” with little in the way of
objective, scientific basis (Table 10-10). The only placebo controlled dietary study, while small, failed to demonstrate a relationship between diet and symptoms (Fisher et al. 1993). Bade
and colleagues found that IC patients tend to have a healthier
diet than the general population, but could discern no rationale for dietary or fluid intake change other than decreasing
caffeine intake (Bade, Peeters, & Mensink 1997). Nguan and
coworkers (Nguan et al. 2005) performed a prospective, double-blind, cross-over study consisting of cross-over instillations of urine at physiological pH (5.0) and neutral buffered
31
Plums
Pomegranates
Rhubarb
Strawberries
Juices from above fruits
Carbohydrates and grains
Rye bread
Sourdough bread
Meats and fish
Aged, canned, cured processed, smoked
meats and fish
Nuts
Beverages
Alcoholic beverages including beer and wine
Carbonated drinks
Coffee
Tea
Fruit juices
Seasonings
Mayonnaise
Ketchup
Mustard
Salsa
Spicy foods: (Chinese, Mexican, Indian, Thai)
Soy sauce
Miso
Salad dressing
Vinegar
Preservatives and additives
Benzyl alcohol
Citric acid
Monosodium glutamate
Artificial sweeteners
Preservatives
Artificial ingredients
Food coloring
Miscellaneous
Tobacco
Caffeine
Diet pills
Junk foods
Recreational drugs
Allergy medications with ephedrine or
pseudoephedrine
Certain vitamins
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
Drug
Amitriptyline
Antibiotic regimens
Anticholinergics and
antispasmodics
Azathioprine
Benzydamine
Chloroquine derivatives
Cimetidine
Cortisone and other steroids
Cyclosporine
Doxycycline
Gabapentin
Hormones
Hydroxyzine
L-Arginine
Methotrexate
Misoprostgil
Montelukast
Nalmefene
Narcotic analgesics
Nifedipine
Phenazopyridine
Quercitin
Sodium pentosanpolysulfate
Suplatast tosilate
Vitamin E
Randomized
Control Trial
% Success
yes
yes
42%
48%
no
no
yes
no
yes
no
no
no
no
no
yes
yes
no
no
no
yes
no
no
no
no
yes
yes
no
anecdotal
50%
0%
50%
65%
80%
90%
71%
anecdotal
anecdotal
31%
not effective
50%
48%
90%
not effective
anecdotal
87%
anecdotal
92%
33%
pending publication
anecdotal
trolled double blind trial of 50 patients, 63% on amitriptyline
at doses of 25-75mg (dose as tolerated) before bed reported
good or excellent satisfaction versus 4% on placebo (van et al.
2004a) (van et al. 2004a). At 19 month follow-up there was little tachyphylaxis and good response rates were observed in the
entire spectrum of PBS/IC symptoms (van Ophoven & Hertle
2005).
Amitriptyline has proven analgesic efficacy with a median
preferred dose of 75mg in a range of 25-150mg daily. This
range is lower than traditional doses for depression of 150300mg. The speed of onset of effect is much faster (one to
seven days) than reported in depression, and the analgesic
effect is distinct from any effect on mood (McQuay HJ &
Moore RA 1997). Tricyclic antidepressants are contraindicated in patients with long QT syndrome or significant conduction system disease (bifascicular or trifascicular block) after
recent myocardial infarction (within 6 months), unstable
angina, congestive heart failure, frequent premature ventricular contractions, or a history of sustained ventricular arrhythmias. They should be used with caution in patients with
orthostatic hypotension (Low & Dotson 1998). Doses greater
than 100mg are associated with increased relative risk of sudden cardiac death (Ray et al. 2004).
AL
Table 10-11. Some of the Oral Medications that
have been used for Treatment of PBS/IC
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Adapted from Incontinence 3rd International Consultation on INCONTINENCE. See text for details.
Hanno and Wein first reported a therapeutic response in
interstitial cystitis after noting a “serendipitous” response to
amitriptyline in one of their patients concurrently being treated for depression (Hanno & Wein 1987). The following year a
similar report appeared relating a response to desipramine
hydrochloride (Renshaw 1988). Reasoning that a drug used
successfully at relatively low dosages for many types of chronic pain syndromes, which would also have anticholinergic
properties, beta-adrenergic bladder
bladder effects, sedative characteristics, and strong H1 antihistaminic activity would seem to be
ideal for interstitial cystitis, the first clinical trial was carried
out with promising results (Hanno, Buehler, & Wein 1989). A
subsequent follow-up study (Hanno 1994b) reported that in
28 of 43 patients who could tolerate therapy for at least a 3
week trial at a dosage of 25mg HS gradually increasing to
75mg HS over 2 weeks, 18 had total remission of symptoms
with a mean follow-up of 14.4 months, 5 dropped out because
of side effects, and 5 derived no clinical benefit. Benefits were
apparent within 4 weeks. All patients had failed hydrodistention and intravesical dimethylsulfoxide therapy. Sedation was
the main side effect. Kirkemo and colleagues treated 30
patients and had a 90% subjective improvement rate at 8
weeks (Kirkemo, Miles, & Peters 1990). Both studies noted
that patients with bladder capacities over 450-600cc under
anesthesia seemed to have the best results. Another uncontrolled study of 11 patients with urinary frequency and pelvic
pain (Pranikoff & Constantino 1998) related success in 9 of
the patients, with 5 reporting complete resolution of symptoms and 4 significant relief. Two patients could not tolerate
the medication. In a 4 month intent to treat placebo con-
Antihistamines
The use of antihistamines goes back to the late 1950's and
stems from work by Simmons who postulated that the local
release of histamine may be responsible for, or accompany the
development of, interstitial cystitis (Simmons 1961). He
reported on 6 patients treated with pyribenzamine. The
results were far from dramatic, with only half of the patients
showing some response. The therapy is notable for this disease
in that it was very logically conceived. It has been Theoharides
who has spearheaded mast cell research in this field and been
a major modern proponent of antihistamine therapy
(Theoharides 1994). He has used the unique piperazine H1receptor antagonist hydroxyzine, a first generation antihistamine (Simons 2004), which can block neuronal activation of
mast cells (Minogiannis et al. 1998). In 40 patients treated
with 25mg before bed increasing over 2 weeks (if sedation was
not a problem) to 50mg at night and 25mg in the morning,
virtually every symptom evaluated improved by 30%. Only 3
patients had absolutely no response. As with many IC drug
reports, these responses were evaluated subjectively and without being blinded or placebo-controlled. A subsequent study
suggested improved efficacy in patients with documented
allergies and/or evidence of bladder mast cell activation
(Theoharides & Sant 1997a; Theoharides & Sant 1997b) . No
significant response to hydroxyzine was found in an NIDDK
placebo controlled trial (Sant, Propert, Hanno, Burks, Culkin,
Diokno, Hardy, Landis, Mayer, Madigan, Messing, Peters,
Theoharides, Warren, Wein, Steers, Kusek, & Nyberg 2003).
Why an H2-antagonist would be effective is unclear, but
uncontrolled studies show improvement of symptoms in twothirds of patients taking cimetidine in divided doses totaling
600mg (Seshadri, Emerson, & Morales 1994; Lewi 1996). It
proved effective in a double blind, placebo controlled trial
(Thilagarajah, Witherow, & Walker 2001), but histologic studies show the bladder mucosa to be unchanged before and after
Sodium Pentosanpolysulfate
Miscellaneous Agents
Several oral therapies for interstitial cystitis have been tried
and essentially been discarded, though some are being reinvestigated. Dees reported temporary improvement with systemic steroids (Dees 1953), but these drugs have not been
found to be useful (Pool 1967), and the risks of chronic
administration are considerable. Prednisone at a dose of 25mg
daily for 1-2 months and then tapered as tolerated may be
effective in patients with otherwise unresponsive ulcerative
disease (Soucy & Gregoire 2005). Hormones have been used
without success (Burford & Burford 1958; Badenoch 1971).
Vitamin E, anticholinergics, and antispasmodics are not generally efficacious (Burford & Burford 1958; Pool 1967).
Immunosuppression and chloroquine derivatives have been
administered (Oravisto & Alfthan 1976). About 50% of
patients responded to some extent, but potential complications are significant and neither therapy has found general
usage. Cyclosporine seemed to have some beneficial effect in a
small, uncontrolled study (Forsell et al. 1996). A follow-up
trial showed benefit in 20 of 23 patients treated for a minimum of one year (Sairanen, Forsell, & Ruutu 2004). Low dose
oral methotrexate improved bladder pain in 4 of 9 patients
and had no effect on voiding pattern (Moran et al. 1999).
Benzydamine, a potent anti-inflammatory drug with strong
analgesic effects was initially reported to have a superb
response rate in IC (Walsh 1976), but a controlled follow-up
trial demonstrated no responses in the first 12 patients, and
the trial was discontinued (Walsh 1977).
The opiate antagonist Nalmefene was tried in an uncontrolled trial with promising results (Stone 1994). It is known
that mast cells degranulate and release histamines and other
mediators when their endogenous opioid receptors are stimulated. In PBS/IC this theoretically could occur because of
chronic endorphin release stimulated by the pain. By blocking
the patient's own endogenous stimulation of mast cell
degranulation, a “vicious cycle” could possibly be broken.
Unfortunately, an unpublished, placebo-controlled trial failed
to demonstrate the hoped-for efficacy.
The calcium channel antagonist nifedipine has been tried
in an uncontrolled study for IC and urethral syndrome
(Fleischmann 1994). Nifedipine has been reported to inhibit
detrusor contractions and depress cell-mediated immune
functions. Of 9 IC patients treated for at least 4 months, 5
showed a 50% decrease in symptom scores and 33% were
asymptomatic. Similar results were noted in patients treated
for urethral syndrome. Misoprostol, an oral prostaglandin
analogue, demonstrated a 48% response in a nine month
open label trial, though 64% of patients experience adverse
drug effects (Kelly et al. 1998). A cytoprotective action was
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Parson's suggestion that a defect in the epithelial permeability
barrier, the glycosaminoglycan (GAG) layer, contributes to the
pathogenesis of IC has lead to an attempt to correct such a
defect with the synthetic sulfated polysaccharide sodium pentosanpolysulfate (PPS), a heparin analogue available in an oral
formulation, 3-6% of which is excreted into the urine
(Barrington & Stephenson 1997). It is sold under the trade
name Elmiron. Studies have been contradictory.
Fritjofsson treated 87 patients in an open multicenter trial
in Sweden and Finland (Fritjofsson et al. 1987). Bladder volume with and without anesthesia was unchanged. Relief of
pain was complete in 35% and partial in 23% of patients.
Daytime frequency decreased from 16.5 to 13 and nocturia
decreased from 4.5 to 3.5. Mean voided volumes increased by
almost a tablespoon in the nonulcer group. Holm-Bentzen
studied 115 patients in a double-blind, placebo controlled
trial (Holm-Bentzen et al. 1987a). Symptoms, urodynamic
parameters, cystoscopic appearance, and mast cell counts were
unchanged after 4 months. Bladder capacity under anesthesia
increased significantly in the group with mastocytosis, but this
had no bearing on symptoms or awake capacity.
Parsons had a more encouraging initial experience
(Parsons, Schmidt, & Pollen 1983), and subsequently the
results of 2 placebo controlled multicenter trials in the United
States were published (Mulholland et al. 1990; Parsons et al.
1993). In the initial study, overall improvement of greater than
25% was reported by 28 per cent of the PPS-treated group
versus 13% in the placebo group. In the latter study the
respective figures were 32% on drug versus 16% on placebo.
Average voided volume on PPS increased by 20cc. No other
objective improvements were documented. An NIDDK 2 X 2
factorial study to evaluate PPS and hydroxyzine looked at each
drug used alone and in combination and compared results to
a placebo group (Sant, Propert, Hanno, Burks, Culkin,
Diokno, Hardy, Landis, Mayer, Madigan, Messing, Peters,
Theoharides, Warren, Wein, Steers, Kusek, & Nyberg 2003).
Patients were treated for 6 months. No statistically significant
response to either medication was documented. No significant trend was seen in the PPS treatment groups (34%) compared to non-PPS groups (18%). Of the 29 patients on PPS
alone, 28% had global response (the primary endpoint) of
moderately or markedly improved vs. 13% on placebo, a
number remarkable similar to the results in the 3 month pivotal trials, although not reaching statistical significance in the
6 month study. A subsequent industry sponsored trial showed
no dose-related efficacy response in the range of 300-900mg
daily, however adverse events were dose-related (Nickel et al.
2005).
Long-term experience with PPS is consistent with efficacy
in a subset of patients that may drop below 30% of those initially treated (Jepsen et al. 1998). Tachyphylaxis seems to be
uncommon in responders. Adverse events with PPS occurred
in less than 4% of patients at the dose of 100mg three times
daily (Hanno 1997) and include reversible alopecia, diarrhea,
nausea and rash. Rare bleeding problems have been reported
(Rice, Kennedy, & Veach 1998). It promotes cellular prolifera-
tion in vitro in the MCF-7 breast cancer cell line, and caution
has been suggested in prescribing it in groups at high-risk for
breast cancer and premenopausal females (Zaslau et al. 2004).
A three to six month treatment trial is generally required to
see symptom improvement. In a small trial, PPS has shown
efficacy when administered intravesically (Bade et al. 1997). It
may be of value in the management of radiation cystitis
(Hampson & Woodhouse 1994; Parsons 1986) and cyclophosphamide cystitis (Toren & Norman 2005), but its value in the
treatment of PBS/IC seems marginal.
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treatment, and the mechanism of any efficacy remains unexplained (Dasgupta et al. 2001).
33
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
postulated as the mode of action. The cysteinyl leukotriene D4
receptor antagonist montelukast, a commonly used allergy
medication, has shown potential benefits in a small, uncontrolled Danish study (Bouchelouche et al. 2001b).
Oral L-arginine, an over-the-counter amino acid preparation, was purported to increase nitric oxide related enzymes
and metabolites in the urine of IC patients and decrease
symptoms (Smith, Wheeler, Foster, Jr., & Weiss 1996; Smith et
al. 1997), perhaps through relaxation of urinary tract smooth
muscle. Later studies showed no change in bladder nitric
oxide concentrations after treatment with L-arginine, or any
significant symptom improvement (Ehren et al. 1998; Korting
et al. 1999). An open-label trial of the over-the-counter oral
bioflavonoid quercitin has suggested some efficacy (Katske et
al. 2001).
Chronic pain patients often receive inadequate doses of
short-acting pain medications, which put them on cycles of
short-term relief, anxiety, and pain. It leads to doctor-shopping and drug-seeking behavior confused by physicians with
drug addiction. While physical dependence to opioids will be
unavoidable, physical addiction, a chronic disorder characterized by the compulsive use of a substance resulting in physical, psychological or social harm to the user and the continued
use despite that harm, is rare. Chronic opioid therapy can be
considered as a last resort in selected patients. It is best administered in a pain clinic setting, requiring frequent reassessment
by both patient and physician (Portenoy & Foley 1986).
Analgesics
Intravesical lavage with one of a variety of preparations has
remained a mainstay of treatment in the therapeutic armamentarium of IC. Perhaps the oldest of the intravesical therapies is silver nitrate. The use of silver nitrate has been attributed to Mercier (Pool & Rives 1944) who reported in 1855
that excellent results with bladder instillations had been
obtained in patients suffering from symptoms compatible
with interstitial cystitis. Dodson advocated the use of solutions of silver nitrate in increasing strengths as the treatment
of choice for this condition (Dodson 1926). Pool and Rives
reported on 74 patients with interstitial cystitis treated with
intravesical silver nitrate. The treatment was carried out as follows:
A urethral catheter is inserted and the contents of the bladder are evacuated. The bladder is then irrigated with a saturated solution of boric acid. Then 30 to 60cc of a 1:5000 solution of silver nitrate is instilled into the bladder and permitted
to remain there for 3 or 4 minutes if it does not cause intolerable irritation. At the end of this period the solution is permitted to run out through the catheter, which is then withdrawn. The patient usually experiences some dysuria and vesical irritability for 2 or 3 hours. Treatments are repeated every
other day. At subsequent treatments, the concentration of silver nitrate in the solution is increased to 1:2500, 1:1000, 1:750,
1:500, 1:400, 1:200, and finally 1:100. If at any time the reac-
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The long-term, appropriate use of pain medications forms an
integral part of the treatment of a chronic pain condition like
interstitial cystitis. Most patients can be helped markedly with
medical pain management using pain medications commonly used for chronic neuropathic pain syndromes including
antidepressants, anticonvulsants, and opioids (Wesselmann,
Burnett, & Heinberg 1997). Many nonopioid analgesics
including acetaminophen and the nonsteroidal anti-inflammatory drugs (NSAIDs) and even antispasmodic agents
(Rummans 1994) have a place in therapy along with agents
designed to specifically treat the disorder itself. Unlike opioids, with increasing doses acetaminophen, aspirin, and the
other NSAIDs all reach a ceiling for their maximum analgesic
effect (Anonymous 1998). Gabapentin, introduced in 1994 as
an anticonvulsant, has found efficacy in neuropathic pain disorders including diabetic neuropathy
opathy (Backonja et al. 1998)
and postherpetic neuralgia (Rowbotham et al. 1998). It
demonstrates synergism with morphine in neuropathic pain
(Gilron et al. 2005). It may gave some benefit in chronic pelvic
pain syndromes and PBS/IC (Sasaki et al. 2001).
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. Opiates are seldom the first choice of analgesics in chronic pain states, but they should not be withheld
if less powerful analgesics have failed (Portenoy et al. 1997;
Bennett 1999). This is a difficult decision that requires much
thought and discussion between patient and urologist, and
involvement of a pain specialist is indicated. A single practitioner has to take responsibility for pain treatment and write
all prescriptions for pain medications (Brookoff 1997).
Opioids are effective for most forms of moderate and severe
pain and have no ceiling effect other than that imposed by
adverse effects. The common side effects include sedation,
nausea, mild confusion, and pruritis. These are generally transient and easily managed. Respiratory depression is extremely
rare if they are used as prescribed. Constipation is common
and a mild laxative is generally necessary. The major impediment to the proper use of these drugs when they are prescribed for long-term nonmalignant pain is the fear of addiction. Studies suggest the risk is low (Gourlay 1994). The longacting narcotic formulations that result in steady levels of
drug over many hours are preferable.
INTRAVESICAL AND INTRADETRUSOR
THERAPY (Table 10-12)
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34
Table 10-12. Some of the intravesical medications
that have been used for treatment of PBS/IC
Drug
RCT
% Success
Silver nitrate
Clorpactin WCS-90
DMSO
BCG
RTX
Hyaluronic acid
Heparin
Chondroitin sulfate
Lidocaine
Capsaicin
Oxybutinin
Doxorubicin
Pentosan polysulfate
no
no
yes
yes
yes
yes
no
no
no
no
no
no
yes
60%
60%
70%
no proven efficacy
no proven efficacy
no proven efficacy
60%
33%
65%
no demonstrated efficacy
efficacy suggested
anecdotal efficacy
40%
See text. Adapted from Incontinence; 3rd International Consultation on
INCONTINENCE
AL
ceptive pathways in the lower urinary tract (Birder, Kanai, &
de Groat 1997). Tests for DMSO for treatment of human illness began in the 1960s in the areas of musculoskeletal
inflammation and the cutaneous manifestations of scleroderma.
Stewart and colleagues are responsible for popularizing
intravesical DMSO for IC (Stewart, Persky, & Kiser 1968). In
the mid 1960s he applied it to the skin over the suprapubic
area in a group of patients refractory to conventional forms of
therapy. Results were poor, but intravesical delivery of 50ml of
a 50% solution instilled for 15 minutes by catheter and repeated at intervals of 2-4 weeks showed positive effects in 6 of 8
patients lasting 2-12 months. The lack of side-effects, other
than a garlic-like odor on the breath, or need for inpatient
administration were significant breakthroughs over previous
treatments. Further reports by this group confirmed safety
and efficacy (Stewart et al. 1971; Stewart et al. 1972; Stewart &
Shirley 1976; Shirley, Stewart, & Mirelman 1978) with symptom-free intervals of 1-3 months in 73% of patients. Ek
reported a 70% success rate, but found most patients ultimately required retreatment or further therapy with other
modalities (Ek et al. 1978). Prospective series of Fowler
(Fowler, Jr. 1981) and Barker et al. (Barker et al. 1987) revealed
symptomatic success rates of greater than 80% although
relapse was not uncommon. Fowler noted only minimal
improvements in functional bladder capacity and attributed
the beneficial effects of DMSO to a direct effect on the sensory nerves of the bladder. Perez-Marrero compared DMSO to
saline and showed a 93% objective improvement and 53%
subjective improvement compared to 35% and 18% respectively for saline (Perez-Marrero, Emerson, & Feltis 1988).
Patients with bladder instability do not respond (Emerson &
Feltis 1986).
With its ease of administration (Biggers 1986), lack of side
effects, and dependable symptomatic results, DMSO certainly
merits its place as a useful treatment for PBS/IC. The author
generally administers 50cc of 50% DMSO as a bladder “cocktail” with 10mg triamcinolone, 40,000 units heparin, and
44meq sodium bicarbonate. In vivo studies on rat bladder
strips exposed to various concentrations of DMSO for 7 minutes showed absence of electrical field stimulation contraction
at a 40% concentration and diminished compliance at 30%
concentration (Melchior et al. 2003). Concentrations of 25%
or less had negligible effects in this model. How it relates to
use of DMSO in humans is unknown. A rare case of
eosinophilic cystitis has been reported after DMSO instillation (Abramov, Goldberg, McGuire, Golden, Gandhi, & Sand
2004).
Exogenous glycosaminoglycans have been shown to be
effective in providing an epithelial permeability barrier in
bladders in which the epithelium has been injured with protamine (Nickel et al. 1998). Heparin, which can mimic the
activity of the bladder's own mucopolysaccharide lining
(Hanno, Fritz, & Wein 1978), has anti-inflammatory effects as
well as actions which inhibit fibroblast proliferation, angiogenesis, and smooth muscle cell proliferation. Because of its
numerous effects, the possibility that heparin could be used
for therapeutic reasons other than the control of coagulation
has been the subject of much inquiry and speculation (Lane &
Adams 1993). Weaver first reported intravesical heparin for IC
treatment (Weaver, Dougherty, & Natoli 1963). Given intrav-
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tion is too severe, the concentration is increased more slowly
(Pool & Rives 1944).
While the initial treatments are performed under general
anesthesia, later treatments are given on an outpatient basis.
Ureteral reflux would be a contraindication, and it goes without saying that bladder biopsy would be contraindicated just
prior to instillation for fear of extravasation. Twenty three
years later, Pool wrote that he still considered this treatment
regimen the most efficacious form of treatment (Pool 1967)
(Pool 1967). Pool reported excellent results in 70% of patients
with a mean response of 7.6 months. Burford reported a 14%
cure rate and 79% improved figure (Burford & Burford 1958).
DeJuana had a 50% response rate in 102 patients (DeJuana &
Everett, Jr. 1977).
O'Conor reported the use of intravesical Clorpactin WCS
90(O'Connor 1955). Clorpactin is a generic term for closely
related, highly reactive chemical compositions having a modified derivative of hypochlorous acid in a buffered base. Its
activity is dependent on the liberation of hypochlorous acid
and its resulting oxidizing effects, wetting and penetrating
properties, and detergency. Wishard treated 20 patients with
0.2% chlorpactin gently lavaged in the bladder for 3-5 minutes without anesthesia, of whom 14 reported subjective
improvement (Wishard, Jr., Nourse, & Mertz 1957).
Murnaghan noted improvement in 14 of 17 patients, though
10 required further treatment during the average 2 year follow-up (Murnaghan, Saalfeld, & Farnsworth 1970). Most
commonly, the treatments are given as described by Messing
and Stamey, using 0.4% solution administered at 10cm water
pressure under anesthesia (Messing & Stamey 1978). Multiple
instillations can be given, with a one month pause after the
first 2 instillations to await a therapeutic response. Their success rate was 72% with average 6 month duration of response.
La Rock noted a 50-55% meaningful improvement rate occurring within 4-6 weeks of treatment (LaRock & Sant 1995). A
case of ureteral fibrosis complicating the treatment prompted
the recommendation that vesicoureteral reflux be considered
a contraindication to the procedure (Messing & Freiha 1979).
Our method of Clorpactin delivery is as follows:
Reflux is excluded with a cystogram. Under anesthesia the
bladder is distended for two minutes at 60-80cm water pressure and emptied. The perineum is shielded with a moistened
towel. A solution of 0.4% freshly prepared Clorpactin (4
grams in 1000cc of sterile water) is instilled by gravity
drainage (the foley catheter held 10cm above the level of the
bladder) in 150-200cc aliquots for a dwell time of 2-3 minutes
and drained by gravity. This continues until the entire 1000cc
solution has been used. The bladder and introitus are then
irrigated with normal saline and the catheter is removed.
A mainstay of the treatment of interstitial cystitis is the
intravesical instillation of dimethylsulfoxide (DMSO) (Sant
1987). DMSO is a product of the wood pulp industry and a
derivative of lignin. It has exceptional solvent properties and
is freely miscible with water, lipids, and organic agents.
Pharmacologic properties include membrane penetration,
enhanced drug absorption, anti-inflammatory, analgesic, collagen dissolution, muscle relaxant, and mast cell histaminerelease. In-vitro effects on bladder function belie its positive
effects in vivo (Freedman et al. 1989), where histamine release
has not been demonstrated after treatment (Stout et al. 1995).
It has been suggested that DMSO actually desensitizes noci-
35
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
tolerated as well as placebo. Even more surprisingly, 8 of 9
BCG responders continued to have an excellent response in all
parameters measured at 27 months of follow-up (Peters et al.
1998). It is unclear how BCG achieved this result, but
immunologic and/or anti-inflammatory mechanisms have
been postulated (Peters, Diokno, & Steinert 1999). A doubleblind crossover Swedish study comparing DMSO to BCG
failed to substantiate BCG efficacy (Peeker et al. 2000c)
(Peeker et al. 2000c). A large multicenter randomized controlled trial by NIDDK comparing BCG to placebo found a
12% response rate for placebo compared to a 21% response
for BCG. The small response rate failed to reach statistical significance at the p=0.05 level, and this large study of 265
patients indicates that BCG has no place in the treatment of
moderate to severe PBS/IC (Mayer & Interstial cystitis clinical
trials group 2005). Though the BCG safety profile was considered acceptable in the NIDDK trial, adverse events were not
uncommon, and rare hypersensitivity reactions to intravesical
BCG can occur (Parker et al. 2004).
Efforts to bring new therapies directly to the bladder continue to be the focus of investigators. Oxybutinin has shown
efficacy in preliminary studies when administered intravesically at doses of 10mg dissolved in saline (Bade et al. 2000;
Barbalias, Liatsikos, Athanasopoulos, & Nikiforidis 2000).
Electromotive drug administration, the active transport of
ionized drugs by the application of an electric current, using
lidocaine and dexamethasone, has shown a 25% success rate
up to 6 months post instillation (Rosamilia, Dwyer, & Gibson
1997). A similar trial using repeated instillations noted success
rates of 60% with a mean duration of 6.6 months (Riedl et al.
1997). Capsaicin, the main pungent ingredient in hot peppers
of the genus Capsicum, is a specific neurotoxin that desensitizes C fiber afferent neurons. Resiniferatoxin (RTX), an ultrapotent analogue of capsaicin, appears to have similar effects
with less of the acute pain and irritation associated with capsaicin application. Both compounds have been tested intravesically for the relief of detrusor overactivitybladder instability and hyperreflexia (Chancellor & de Groat 1999). Clinical
trials for the use of these compounds in bladder pain,
urgency/frequency could show this to be a new and viable
treatment modality in the future, but current data on efficacy
in IC are lacking (Lazzeri et al. 1996; Cruz et al. 1997; Lazzeri
et al. 2000). An unpublished phase 2 safety and proof of concept multicenter, placebo-controlled trial conducted by ICOS
Corporation of Bothell, WA found no significant efficacy of
RTX compared with placebo, although no safety issues were
identified (Interstitial Cystitis Association 2004).
The therapeutic value of botulinum toxin type A (BTX-A)
stems partially from its ability to temporarily inhibit acetylcholine release and cause flaccid paralysis in a dose related
manner. It can correct focal dystonia when injected into a
muscle. In recent years there has been increasing evidence that
BTX-A might also have analgesic properties (Rajkumar &
Conn 2004). Initially this was thought to be due to relief of
muscle spasm. However, botulinum has been shown to reduce
peripheral sensitization by inhibiting the release of several
neuronal signaling markers, including glutamate and substance P, and reducing c-fos gene expression. It may affect the
sensory feedback loop to the central nervous system by
decreased input from the muscle tissue, possibly by inhibiting
acetylcholine release from gamma motor neurons innervating
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esically, there is virtually no systemic absorption, even in an
inflamed bladder (Caulfield, Phillips, & Steinhardt 1995).
While uncontrolled studies suggested some beneficial effect
for subcutaneous administration (Lose et al. 1983; Lose et al.
1985), the obvious risks of anticoagulation and osteoporosis
have prevented this form of administration from undergoing
further trials and general usage. Ten thousand units can be
administered intravesically in sterile water either alone or with
DMSO at varying intervals with good results reported (PerezMarrero et al. 1993; Parsons et al. 1994a). Kuo reported 50%
or more improvement in the International Prostate Symptom
Score in 29 of 40 women with IC treated with 25,000 units
intravesically twice weekly for 3 months (Kuo 2001). Parsons
has used daily intravesical doses of 40,000 units of heparin in
20cc sterile water administered by the patient daily and held
for 30-60 minutes. “Reasonable improvement of symptoms”
can be expected between 6 months and 2 years after starting
therapy (Parsons 2000). Adding alkalinized lidocaine to the
heparin instillation provides better pain relief (Parsons 2005).
These encouraging outcomes must be kept in perspective,
given that they are unproven by any placebo-controlled trial.
Another GAG analogue, pentosanpolysulphate, administered intravesically 300mg twice weekly in 50ml of normal
saline, showed some modest benefit in a small trial (Bade,
Laseur, Nieuwenburg, van der Weele, & Mensink 1997). The
nonsulfated GAG, hyaluronic acid, has also been used intravesically. Trials using 40mg dissolved in 40cc normal saline
weekly for 4-6 weeks, and then monthly treatments thereafter
have had response rates varying from 71% (Morales,
Emerson, Nickel, & Lundie 1996) to 30% (Porru et al. 1997).
In the summer of 2003 Bioniche Life Science Inc.(Interstitial Cystitis Association 2003) http://www.ichelp.com/research/Prelim-inaryCystistatTrialResults.html and in the
spring of 2004 Seikagaku Corporation http://www.ichelp
.com/research/NovelTherapyNotEffective.html reported double blind, placebo-controlled, multicenter clinical studies of
their hyaluronic acid preparations (40mg or 200mg per cc
respectively) and neither showed significant efficacy of sodium hyaluronate compared to placebo (2004). These negative
studies have not been published in peer reviewed literature.
Neither preparation has been approved for use for PBS/IC in
the United States.
Hurst has shown by immunohistochemistry a deficit of
chondroitin sulfate from the luminal bladder surface in IC
patients (Hurst 2003). Small uncontrolled studies using
intravesical chondroitin sulfate have shown success rates of
33% (Steinhoff, Ittah, & Rowan 2002) to 50% (Sorensen
2003).
Doxorubicin (Khanna & Loose 1990) and the mast cell stabilizer cromolyn sodium (Edwards, Bucknall, & Makin 1986;
Kennelly & Konnak 1995) have been tried in pilot trials with
the promising results we come to expect in such studies.
Follow-up studies are lacking, and these drugs have not
become a part of the intravesical pharmacopoeia.
The use of intravesical bacillus Calmette-Guerin (BCG) for
interstitial cystitis was first reported by Zeidman and colleagues (Zeidman et al. 1994). A subsequent randomized,
prospective, double-blind, placebo controlled trial of 30
patients treated weekly for 6 weeks and followed for a mean of
8 months noted a 60% response rate compared to a 27%
placebo response (Peters et al. 1997). Surprisingly, BCG was
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AL
Acupuncture has been used to treat frequency, urgency and
dysuria (Chang 1988). Twenty-two of 26 patients treated at
the Sp. 6 point had clinically symptomatic improvement. A
study looking at both acupuncture and TENS in IC showed
limited effects of both modalities (Geirsson, Wang,
Lindstrom, & Fall 1993). Lumbar epidural blockade is the
subject of a positive recent case report (Pelaez et al. 2004), but
in an earlier series resulted in only short-term (mean 15 days)
pain relief in IC (Irwin, Hammonds, & Galloway 1993).
Posterior tibial nerve stimulation was successful in 60% of 37
patients with symptoms of bladder overactivity in an uncontrolled Dutch study (van Balken et al. 2001). An Australian
double-blind placebo controlled study of transdermal posterior tibial nerve laser therapy for interstitial cystitis showed no
benefit in 56 patients when comparing active to placebo arms,
but the placebo effect was remarkably strong, indicating the
importance of such trials when evaluating invasive therapies
(O'Reilly, Dwyer, Hawthorne, Cleaver, Thomas, Rosamilia, &
Fynes 2004).
Direct sacral nerve stimulation has recently been explored
in the treatment of interstitial cystitis and urgency/frequency,
and is referred to as neuromodulation, a technique whose
urologic potential was developed through the basic and clinical research of Schmidt (Schmidt 1993). He and others have
observed that patients who do best with this treatment modality are those who have identifiable pain and dysfunction in the
pelvic muscles (Everaert et al. 2001; Siegel et al. 2001; Aboseif
et al. 2002). Those patients reporting pelvic pain in the
absence of demonstrable pelvic floor dysfunction and levator
tenderness did poorly (Schmidt 2001). As initially practiced,
trial stimulation was performed with a percutaneous temporary electrode for a 3 to 4 day temporary stimulation period
to access efficacy. The S3 nerve is most frequently used. A wire
electrode is inserted into the foramen and connected to an
external pulse generator (Medtronic Inc., Minneapolis,
Minnesota, USA). If the trial is successful, the patient would
be considered for implantation of a permanent neural prosthesis. More recently, a staged procedure has supplanted the
traditional percutaneous approach, as the response to stimulation can be better assessed with more accurate lead placement and stability than through the more hit or miss percutaneous lead placement (Peters, Carey, & Konstandt 2003).
Peters’ test to implant rate increased from 52% to 94%. Other
reports have noted a test to implant rate in the percutaneous
technique from 76% in 33 PBS/IC patients (Whitmore et al.
2003) to 40% in 211 patients with refractory urge incontinence, urgency-frequency syndrome, and urinary retention
(Scheepens et al. 2002).
Neuromodulation has been shown to be effective in treating refractory urinary urge incontinence (Schmidt et al. 1999;
Spinelli et al. 2001). Studies on therapeutic potential in
PBS/IC followed (Van Kerrebroeck 1999). The University of
Maryland group described decrease in antiproliferative activity and normalization of HB-EGF levels in patients with successful test stimulation (Chai, Zhang, Warren, & Keay 2000a).
Peters and coworkers reported success in two-thirds of PBS/IC
patients with sacral nerve stimulation (Peters, Carey, &
Konstandt 2003). Comiter (Comiter 2003) found 17 of 25
patients were successful with test stimulation and went on to
permanent implantation of the Interstim device (Medtronics,
St. Paul, MN). Thirteen of 15 who underwent staged implan-
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intrafusal fibers of the muscle spindle (Rosales, Ariumura, &
Ikenaga 1996). BTX-A has been used effectively for years in
different conditions with muscular hypercontractions.
Intradetrusorvesical BTX administration blocks the acetic
acid-induced calcitonin gene-related peptide (CGRP) release
from afferent nerve terminals in the bladder mucosal layer in
rats (Chuang et al. 2004). In an animal model of bladder permeability barrier disruption, intradetrusorvesical BTX-A
minimized bladder irritability and restored afferent neural
responses to baseline levels (Vemulakonda et al. 2005). These
results support clinical trials of BTX-A for the treatment of
PBS/IC and other types of visceral pain (Chancellor &
Yoshimura 2004).
A multi-institutional case series using Botox or Dysport
intradetrusorvesical injections in 13 patients with refractory
PBS/IC reported improvement in 9 patients. Improvements in
symptoms lasted a mean of 3.72 months (mean 1-8 months).
No systemic complications were observed, though 2 patients
had a diminished flow with some need to strain to void
(Smith et al. 2004). Rackley and colleagues at the Cleveland
Clinic reported no change in objective or subjective outcome
measures in a series of 10 PBS/IC patients in whom the
trigone was spared in the injection technique (Rackley, Frenkl,
& Abdelmalak 2005). At this time, Botox can only be recommended for PBS/IC use only in the context of carefully controlled clinical trials.
Neuromodulation
As a chronic pain syndrome, it is reasonable to consider therapeutic options that directly interface
erface 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 (Zermann, Ishigooka, Doggweiler, & Schmidt
1999).
Pain diversion by transcutaneous electrical nerve stimulation (TENS) is routine in a variety of painful conditions (Fall
1987). Fall and colleagues were the first to use electrical stimulation in interstitial cystitis, reporting on 14 women treated
successfully with long-term intravaginal or TENs (Fall,
Carlsson, & Erlandson 1980). Subsequently McGuire noted
improvement in 5 of 6 patients treated with electrical stimulation (McGuire et al. 1983).
The primary intention in applying peripheral electrical
nerve stimulation in IC is to relieve pain by stimulating myelinated afferents in order to activate segmental inhibitory circuits. As a secondary effect, urinary frequency may also be
reduced. In the most complete review of the subject to date
(Fall & Lindstrom 1994) 33 patients with ulcerative IC and 27
patients with nonulcerative IC treated by means of suprapubic TENS. Electrodes were positioned 10-15 cm apart immediately above the pubic symphysis. High or low frequency (250 Hz) TENS was employed. If there was no effect with high
frequency after 1 month, low frequency was used. Thirty to
120 minutes of TENS was prescribed daily. Pain improved
more than frequency. Good results or remission were
described in 26% of nonulcer patients and a surprising 54%
of patients with ulcerative disease. The authors caution that
the experience is based on open studies, relatively few patients,
and the knowledge of a significant placebo effect with peripheral pain stimulation.
37
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
Hydrodistention
Hydrodistention of the bladder under anesthesia, while technically a surgical treatment, is often the first therapeutic
modality employed, often as a part of the diagnostic evaluation. Since there have been no standard methods of distention, results vary markedly. Frontz first suggested hydraulic
overdistention of the bladder for IC in 1922(Frontz 1922) ,
and Bumpus reported the first series 8 years later (Bumpus
1930). Simple bladder filling at cystoscopy will give relief to
some patients (Hald, Barnard, & Holm-Bentzen 1986), while
Dunn reported on 25 patients distended under anesthesia to
the level of the systolic blood pressure for up to 3 hours
(Dunn et al. 1977). Sixteen of the patients were symptom free
with a mean follow-up of 14 months; 2 patients suffered bladder rupture. The bladder in IC patients can be very thin and
the possibility of perforation or rupture must always be kept
in mind and discussed with the patient (Badenoch 1971;
Hamer, Nicholson, & Padfield 1992). Prolonged distention
probably has little or no benefit over a short-term distention
measured in minutes (Taub & Stein 1994; McCahy & Styles
1995). Using epidural anesthesia and a balloon distention
technique to the mean arterial pressure for 3 hours continuously, Glemain and colleagues (Glemain et al. 2002) reported
good but transient efficacy in patients with a bladder capacity
of greater than 150cc on predistention cystometry. In their
prospective series of 30 patients, 18 had maintained a therapeutic response at 6 months and 13 at one year of follow-up.
Moderate hematuria was almost universal, worsening of
symptoms occurred in 5% of patients, and low back and
hypogastric pain were common sequelae. There was one bladder rupture, one episode of sepsis, and one episode of prolonged retention.
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 80cm 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 distention. Therapeutic
responses in patients with a bladder capacity under anesthesia
of less than 600cc showed 26% with an excellent and 29%
with a fair result compared with 12% excellent and 43% fair
in patients with larger bladder capacities (Hanno & Wein
1991). Most favorable responses were extremely brief, however, with the exceptional patient noting improvement for 6
months, thus being a candidate for repeat therapeutic distention.
Acute hydrodistention does not seem to result in any longterm bladder dysfunction (Kang, Wein, & Levin 1992; Lasanen
et al. 1992). Any efficacy is probably related to damage to
mucosal afferent nerve endings (Dunn, Ramsden, Roberts,
Smith, & Smith 1977). It has no benefits in patients with
detrusor hyperreflexia or instability (Taub & Stein 1994;
McCahy & Styles 1995). Over half of men with prostate pain
and without bacteriuria may have glomerulations. Symptoms
in this group have been reported to improve with hydrodistention (Berger, Miller, Rothman, Krieger, & Muller 1998) .
While many patients with interstitial cystitis have sensory
urgency at awake capacities of less than 100cc, hydrodistention under anesthesia seems to allow for “staging” of the disease, giving the clinician some idea of the capacity he or she
has to work with conservative therapies. A capacity under
anesthesia of under 200cc would not bode well for the likelihood of success of medical therapy. Fortunately, these cases
are relatively rare.
SURGICAL THERAPY
The surgical therapy of interstitial cystitis is an option after all
trials of conservative treatment have failed; a point which cannot be over-emphasized. Interstitial cystitis, although a cause
of significant morbidity, is a non-malignant process with a
temporary spontaneous remission rate of up to 50% (Held,
Hanno, & Wein 1990) which does not directly result in mortality. Deaths are either self-inflicted or the complications of
therapy. Nowhere does the caveat “primum non nocere” bear
more relevance; the treatment must be no worse than the disease process (Siegel, Snyder, & Raz 1990). Surgery should be
reserved for the motivated and well-informed patient who
falls into the category of extremely severe, unresponsive disease, a group which comprises under 10% of patients (Irwin
& Galloway 1994; Parsons 2000).
Many surgical approaches have been employed for interstitial cystitis, and it is worth mentioning a few for historical perspective alone. Sympathectomy and intraspinal alcohol injections have been used to treat pelvic pain (Greenhill 1947).
Differential sacral neurotomy was reported in 3 patients with
good results (Meirowsky 1969), but like most deinnervation
procedures, never gained popularity because of subsequent
poor results. Transvesical infiltration of the pelvic plexuses
with phenol failed in 5 of 5 patients with IC (Blackford et al.
1984). With a significant complication rate of 17%
(McInerney et al. 1991) it is rarely if ever currently usedd for
sensory urgency disorders or detrusor hyper-reflexia. There
are several reports on cystolysis going back to Richer in
1929(Bourque 1951). Worth and Turner-Warwick reported
some short-term benefit, but unpredictable long-term results
(Worth & Turner-Warwick 1973; Worth 1980). Freiha and
Stamey used it in 6 IC patients with good results in 4 (Freiha
& Stamey 1979). Albers reported long-term follow-up in 11
IC patients and had only 1 success (Albers & Geyer 1988).
Denervation procedures have a notoriously high late-failure
rate, and the procedure is not justified for interstitial cystitis
(Walsh 1985; Stone 1991). In fact, Rogers has concluded that
there exist no convincing clinical studies to recommend surgical procedures to interrupt visceral nerve pathways in women
suffering with any type of chronic pelvic pain (Rogers 2003).
Transurethral resection of a Hunner's ulcer, as initially
reported by Kerr, can provide symptomatic relief (Kerr, Jr.
1971). Fall resected ulcerated lesions in 30 patients resulting in
initial disappearance of pain in all and a decrease in urinary
frequency in 21(Fall 1985). Similar results have been attained
AL
tation were permanently implanted vs. 4 of 10 undergoing
percutaneous test stimulation. With a mean follow-up of 14
months, 16 of 17 patients were judged successful, giving intent
to treat success rate of 64%. While sacral neuromodulation
can decrease narcotic requirements significantly in refractory
PBS/IC, the majority of patients taking chronic narcotics for
pain will likely continue to use them for pain relief even after
implantation (Peters & Konstandt 2004).
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patient treated for bladder contraction from tuberculous cystitis, it can be a painful disaster in the IC patient. Nurse and
colleagues (Nurse, Parry, & Mundy 1991) have gone one step
further, recommending trigone biopsy prior to substitution
cystoplasty. Diversion and /or total cystourethrectomy is recommended if the trigone is “affected” by IC. It is not clear how
this is determined histologically, as IC has no pathognomonic
findings by histology, and generally is not a localized process.
Nielsen and coworkers (Nielsen, Kromann-Andersen, Steven,
& Hald 1990) described 8 women treated with substitution
cystoplasty. Six patients failed, and the results of postoperative
biopsies from the trigone showed no difference in the amount
of fibrosis, degree of degenerative changes in the muscle, and
mast cell density between the 2 cured patients and the others.
There has been a controversy over whether the IC process
can occur in a transposed bowel patch (McGuire, Lytton, &
Cornog, Jr. 1973; Kisman, Nijeholt, & van Krieken 1991; Singh
& Thomas 1996). If so, not only would this be a relative contraindication to the procedure, but it would also provide support for the view that a substance in the urine might be
involved in pathogenesis. There is, however, evidence that
inflammation and fibrosis are the usual reactions of bowel to
exposure to urine, and therefore, pathologic findings alone
would not be conclusive of spread of IC in those patients
(MacDermott, Charpied, Tesluk, & Stone 1990).
Augmentation cystoplasty has many potential complications from the rare incidence of bladder neoplasm (Golomb et
al. 1989) to the more common complication of upper tract
obstruction (Cheng & Whitfield 1990). In the best of hands
complications can involve almost 50% of patients, requiring
surgical intervention in 25% (Khoury et al. 1992;
Bunyaratavej et al. 1993). While problems are more common
in patients operated upon for disorders other than IC, the
risk-benefit ratio of substitution cystoplasty seems to have
discouraged its use in the last several years.
Urinary diversion with or without cystourethrectomy is the
ultimate surgical answer to the dilemma of interstitial cystitis,
akin to cutting the “Gordian Knot”. If diversion alone is chosen, one must keep in mind potential problems that can befall
the remaining bladder including pyocystits, hemorrhage,
severe pain, and unremitting feelings of incomplete emptying
and spasm (Eigner & Freiha 1990; Adeyoju et al. 1996).
Bladder carcinoma has also been reported after urinary diversion, but is not specifically associated with IC (Hanno &
Tomaszewski 1982). Cystourethrectomy is certainly indicated
in patients who are miserable and have not only failed all
other therapies, but have demonstrated chronicity such that
remission is considered extremely unlikely. Fortunately few
patients fall into this category. Theoretically, conduit diversion
seems to be reasonable if one is concerned about disease
occurring in any continent storage type of reconstruction.
The extended simple cystectomy performed for intractable IC
may lend itself to anterior enterocele formation from weakening of the anterior vaginal wall, and prevention of this entity
is warranted at the time of cystectomy (Anderson et al. 1998).
Bejany and Politano reported excellent results in 5 patients
treated with total bladder replacement and recommend
neobladder reconstruction (Bejany & Politano 1995).
Keselman et al had 2 failures in 11 patients treated with continent diversion and attributed this to surgical complications
(Keselman et al. 1995). A Finnish group noted failure in 2 of 4
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with the neodymium-yag laser (Shanberg, Baghdassarian, &
Tansey 1985; Shanberg 1989; Rofeim et al. 2001). Extreme
caution is critical if using a laser in an IC bladder, as forward
scatter through these thin bladders with resulting bowel
injury is an ever-present danger. There would seem to be no
justification in the literature for using the laser to treat areas
of glomerulation or in the nonulcerative form of the disease
(Shanberg & Malloy 1997).
Supratrigonal cystectomy and the formation of an
enterovesical anastomosis with bowel segments has been a
popular surgical procedure for intractable interstitial cystitis.
The diseased bladder is resected in its entirety, sparing only a
1-cm cuff around the trigone to which the bowel segment is
anastomosed (Worth & Turner-Warwick 1972; Irwin &
Galloway 1994). While it is not always clear in the literature
how much bladder has been resected, the results reported
using these procedures for IC have been mixed at best.
Badenoch operated on 9 patients with 4 becoming much
worse, and 3 ultimately undergoing urinary diversion
(Badenoch 1971). Flood and colleagues reviewed 122 augmentation procedures, 21 of which were done for IC. Patients
with IC had the poorest results of any group with only 10 having an “excellent” outcome (Flood et al. 1995). Wallack reported 2 successes (Wallack, Lome, & Presman 1975); Seddon had
success in 7 of 9 patients (Seddon, Best, & Bruce 1977); and
Freiha ended up performing formal urinary diversion in 2 of
6 patients treated with augmentation cecocystoplasty (Freiha,
Faysal, & Stamey 1980). Weiss had success in 3 of 7 patient
treated with sigmoidocystoplasty (Weiss, Wein, & Hanno
1984), and Lunghi had no excellent results in two patients
with IC (Lungi et al. 1984). Webster reviewed his data in 19
patients, and concluded that only patients with bladder capacities under anesthesia less than 350cc should undergo substitution cystoplasty (Webster & Maggio 1989). Hughes lowered
the threshold to less than 250cc (Hughes et al. 1995).
More recent series on subtotal cystectomy plus augmentation have been somewhat more positive (Costello, Crowe, &
Agarwal 2000; Chesa et al. 2001). Peeker had good results in all
10 patients with ulcerative interstitial
interstitial cystitis, but poor results
in the three patients operated upon with nonulcerative disease
(Peeker, Aldenborg, & Fall 1998). He no longer performs the
procedure in the latter group. Linn had success in 20 of 23
patients (only two with ulcerative IC) treated with subtotal
cystectomy and orthotopic bladder substitution with an ileocecal pouch (Linn et al. 1998). He recommends a supratrigonal cystectomy. A Spanish series reported success in 13 of 17
procedures with a mean follow-up of 94 months (Rodriguez
Villamil et al. 1999). The University of Alabama group reported long-term success in 1 of 4 patients with orthotopic
neobladders and 1 0f 3 with augmentation cystoplasty (Lloyd
1999). A German report on substitution cystoplasty sparing
the trigone was quite enthusiastic; detailing a 78% pain-free
rate in 18 patients treated with ileocecal augmentation (10) or
ileal substitution (8) at a mean follow-up of 57 months (van,
Oberpenning, & Hertle 2002). Two patients failed to get any
pain relief and 4 required either long-term intermittent
catheterization or suprapubic drainage to empty the neobladder.
Not all patients empty the bladder spontaneously after substitution cystoplasty. While the need for clean intermittent
catheterization would not obviate a successful outcome in the
39
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
patients treated with cystectomy and conduit diversion
because of persistent pain (Lilius, Oravisto, & Valtonen 1973).
Baskin and Tanagho also cautioned about persistence of
pelvic pain after cystectomy and continent diversion, discussing 3 such patients (Baskin & Tanagho 1992). A similar
report followed (Irwin & Galloway 1992). Webster and
coworkers (Webster et al. 1992) had 10 failures in 14 patients
treated with urinary diversion and cystectourethrectomy. Ten
patients had persistent pelvic pain, and four of them also
Symptoms
Basic
assessment
First line
treatment
Bladder pain
Urinary frequency
Nocturia
with or without
urgency
History
Frequency/volume chart
Focused physical
Examination
Urinalysis, culture,
cytology
'SIMPLE PBS'
Conservative treatment
Patient education
Dietary manipulation
Nonprescription analgesics
Pelvic floor relaxation
Inadequate
improvement
Consider
oral and/or
intravesical
treatments
Second
line
treatment
Inadequate
improvement
Consider:
Cystoscopy under anesthesia
with hydrodistention;
Fulgeration or resection of
Hunner's ulcer if present
Inadequate
improvement
Improved with acceptable
quality of life: Follow
and Support
Consider other
tests
Imaging
Endoscopy
Urinary
infection
Test and
reassess
'Complicated PBS'
Incontinence
UTI's
Haematuria
Gynecologic
signs/symptoms
AL
Painful
bladder
syndrome
complained of pouch pain. Only two patients had symptom
resolution. An English study of 27 patients who underwent
cystectomy and bladder replacement with a Kock pouch noted
successful treatment of pain in all patients, but follow-up was
limited (Christmas, Holmes, & Hendry 1996). Parsons suggests that pouch pain will occur in 40%-50% of patients within 6-36 months of surgery (Parsons 2000).
Attempts have been made to improve results by limiting
the operation to those without detrusor mastocytosis (Trinka,
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Consder:
Pain clinic referral
Neuromodulation
Experimental protocols
inadequate
improvement
Consider:
Diversion with or without
cystectomy
Substitution cystoplasty
Normal
Consider:
Urine cytology
Further imaging
Endoscopy
Urodynamics
Abnormal
Treat as
indicated
Improved with acceptable
quality of life: Follow
and Support
Figure 10–12. Suggested diagnosis and
treatment algorithm. (from Hanno PM,
Baranowski A, et.al: Painful bladder syndrome (including interstitial cystitis); in
Incontinence, volume 2; Abrams P,
Cardozo L, Khoury S, Wein A (eds); Health
Publications Ltd 2005, Editions 21, Paris,
France; pp 1456-1520.)
KEY POINTS
HISTORY/INITIAL ASSESSMENT
Men or women with bladder pain, with or without a
sensation of urgency, often with urinary frequency
and nocturia (especially if drinking a normal amount
of fluids) and no abnormal gynecologic findings to
explain the symptoms should be evaluated for
PBS/IC. The initial assessment consists of a frequency/volume chart, focused physical exam, urinalysis,
and urine culture. Cytology and cystoscopy are recommended if clinically indicated.
Patients with infection should be treated and
reassessed. Those with recurrent urinary infection,
abnormal urinary cytology, and hematuria are evaluated with appropriate imaging and endoscopic procedures, and only if findings are unable to explain the
symptoms are they diagnosed with PBS/IC.
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INITIAL TREATMENT
Patient education, dietary manipulation, nonprescription analgesics, and pelvic floor relaxation techniques
comprise the initial management of PBS/IC. When
these fail, or symptoms are severe and conservative
management unlikely to succeed, oral medication or
intravesical treatment can be prescribed.
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Stanley, Noble, & et.al. 1993) and those without “neuropathic
pelvic pain” (Lotenfoe, Christie, Parsons, Burkett, Helal, &
Lockhart 1995). Based on the experience of the past decades,
it is unclear if these efforts will prove any more successful. It
would seem that risks of failure peculiar to interstitial cystitis
include both the development of pain over time in any continent storage mechanism that is constructed, and the risk of
phantom pain in the pelvis that persists despite the fact that
the stimulus that initially activated the nociceptive neurons
(diseased bladder) has been removed (Cross 1994). Brookhoff
(Brookoff 1997) has proposed trying a differential spinal
anesthetic block before considering cystectomy. If the patient
continues to perceive bladder pain after a spinal anesthetic at
the T10 level, it can be taken as an indicator that the pain signal is being generated at a higher level in the spinal cord and
that surgery on the bladder will not result in pain relief. Some
patients with intractable urinary frequency will opt for simple
conduit urinary diversion alone, feeling that their quality of
life will be improved independent of the pain piece of the puzzle. Despite all of the problems, many patients will do well
after major surgery, and quality of life can measurably
improve (Rupp et al. 2000). In the event of neobladder pain
after subtotal cystectomy and enterocystoplasty or continent
diversion, it appears safe to retubularize a previously used
bowel segment to form a urinary conduit for a straightforward urinary diversion without significant risk of conduit
pain (Elzawahri et al. 2004).
Forty years ago Pool recognized that “...surgical treatment
has not been the boon many had hoped it would be” (Pool
1967). “Diversion of the urine is not the entire answer to the
situation. Removal of the lesion in the bladder has been of no
benefit. Likewise, removal of almost the entire mobile portion
of the bladder proved to be a failure.” Blaivas (Blaivas et al.
2005) and colleagues described results of augmentation enterocystoplasty and continent diversion in 76 consecutive
patients with benign disease with a mean 9 year follow-up. All
7 patients with the diagnosis of interstitial cystitis were classified as failures while 67 of the remaining 69 patients were
cured or improved. When one of the dean's of major urologic reconstruction writes, “I find it very difficult to justify such
extensive surgery (continent diversion, cystourethrectomy)
with such limited results and for these reasons have not been
involved in surgery for IC over the past 3 years” (Webster
1993), it is obvious that one should think carefully and proceed with surgery only after a complete discussion with a very
motivated and well-informed patient.
41
PRINCIPALS OF MANAGEMENT
The information currently available in the literature does not
lend itself to easily formulating a diagnostic or treatment
guideline. Different groups of “experts” would undoubtedly
create different “best practices”. The compromise approach
devised by a an experienced cross-section of urologists and
gynecologists from around the world at the International
Consultation on Continence 2004 meeting in Monaco
(Hanno, Baranowski, Fall, Gajewski, Nordling, Nyberg,
Ratner, Rosamilia, & Ueda 2005) seems reasonable and allows
for significant latitude in individual practice and to account
for patient preference (Fig 10-12).
SECONDARY ASSESSMENT
If initial oral or intravesical therapy fails, or before
beginning such therapy, it is reasonable to consider
further evaluation which can include urodynamics,
pelvic imaging, and cystoscopy with bladder distention and possible bladder biopsy under anesthesia.
Findings of bladder overactivity suggest a trial of
antimuscarinic therapy. Findings of a Hunner’s ulcer
suggest therapy with transurethral fulguration or
resection of the ulcer. Distention itself can have therapeutic benefit in up to one-third of patients, though
benefits rarely persist for longer than a few months.
REFRACTORY PBS/IC
Those patients with persistent, unacceptable symptoms despite oral and/or intravesical therapy are candidates for more aggressive modalities. These might
include 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 (substitution) cystoplasty and urinary
diversion with or without cystectomy have been used
as a last resort with good results in selected patients.
A PHILOSOPHY OF MANAGEMENT
This author believes that, because of the natural history of the disorder, it is best to cautiously progress
through a variety of treatments. Whereas the shotgun
approach, starting newly diagnosed patients on a vari-
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
URETHRAL SYNDROME
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 female
urethra” (Charlton 1986). The term urethral syndrome was
first mentioned in a clinicopathologic study of the female urethra in 1949(Powell & Powell 1949). It appeared in the British
literature in 1965 when a group of New Zealand physicians
used it to describe the 50% of their female patients with urinary symptoms without demonstrable infection (Gallagher,
Montgomerie, & North 1965). 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. Although the symptoms are typically
Table 10-13.
thought to occur in women, there is no reason to assume that
a similar entity does not occur in men (Bodner 1988; Hanno
1995; Gittes & Nakamura 1996). The frequency, urgency, and
suprapubic, perineal and low back pain of the chronic pelvic
pain syndrome in men are certainly reminiscent of the urethral syndrome (Fowler 1989; Gittes 2002).
The urethral syndrome has been subdivided into an acute
and a chronic condition. In the past, dysuric women with
midstream urine cultures containing 105 bacteria/ml or
greater were usually considered to have cystitis, and those with
lower-count bacterial cultures were said to have the urethral
syndrome. Since about 1980, it has become apparent that
infections of the urethra, urinary bladder, and vagina account
for a large proportion of patients who develop the symptom
complex acutely. Therefore, the term acute urethral syndrome,
implying as it does a mysterious cause and a urethral origin of
the malady, has largely been abandoned in favor of identifiable etiologic diagnoses (Latham & Stamm 1984; Hooton
1988), many of which are found in the chapters on urinary
tract infection and sexually transmitted diseases. Only a relatively small percentage of patients with acute urethral syndrome are found on investigation to have no cause for the
symptoms (Stamm, Wagner, Amsel, & et.al. 1980; Stamm
1987). It would be more accurate to categorize this group of
patients by their symptoms than to give them a diagnosis of
“acute urethral syndrome”, which ultimately communicates
little about the disorder.
Those patients with chronic symptoms and with no apparent cause constitute the chronic urethral syndrome category.
This phantom diagnosis is one of exclusion and is rearely used
in modern urologic texts. The symptomatic manifestations of
IC and the chronic urethral syndrome are indistinguishable
(Hanno 1995; Fowler 1989).
The concept of the urethral syndrome, chronic or acute, is
now essentially a historical one, and one no longer alluded to
in the modern medical literature. Some of the many causes of
urinary frequency and urgency are listed in Table 10-13.
AL
ety of simultaneous medications, seems to have many
adherents, employing (or adding) one treatment at a
time makes the natural history of the disease itself an
ally in the treatment process. 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. Dogmatic restriction and diet are
to be avoided unless they are shown to improve symptoms in a particular patient.
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Causes of Frequency and Urgency
Interstitial cystitis
Upper motor neuron lesion
Habit
Large fluid intake
Pregnancy
Bladder calculus
Urethral caruncle
Radiation cystitis
Large post void residual
Genital condyloma
Diabetes mellitus
Cervicitis
Periurethral gland infection
Atrophic urethral changes
Chemical irritants: contraceptive foams, douches
Urinary tract infection
Chemical irritants: contraceptive foams, douches, diaphragm, obsessive
washing
Overactive bladder
Vulvar carcinoma
Diuretic therapy
Bladder cancer
Urethral diverticulum
Pelvic mass
Chemotherapy
Bacterial urethritis
Renal impairment
Diabetes insipidus
SUGGESTED READINGS
Buffington, C. A., Chew, D. J., & DiBartola, S. P. 1999, “On the definition of
feline interstitial cystitis”, J Am.Vet.Med Assoc, vol. 215, no. 2, pp. 186-188.
Elbadawi, A. 1997, “Interstitial cystitis: a critique of current concepts with a
new proposal for pathologic diagnosis and pathogenesis”, Urology, vol. 49,
no. 5A Suppl, pp. 14-40.
Fall, M., Johansson, S. L., & Aldenborg, F. 1987, “Chronic interstitial cystitis: a
heterogeneous syndrome”, J Urol., vol. 137, no. 1, pp. 35-38.
Hand, J. R. 1949, “Interstitial cystitis: report of 223 cases (204 women and 19
men)”, Journal of Urology, vol. 61, pp. 291-310.
Hanno, P., Baranowski, A., Fall, M., Gajewski, J. B., Nordling, J., Nyberg, L.,
Ratner, V., Rosamilia, A., & Ueda, T. 2005, “Painful bladder syndrome
(including interstitial cystitis),” in Incontinence, 3 edn, P. H. Abrams, A. J.
Wein, & L. Cardozo, eds.. Health Publication Ltd, Paris; Chapter 23, 14551520.
Keay, S. & Warren, J. W. 1998, “A hypothesis for the etiology of interstitial cystitis based upon inhibition of bladder epithelial repair”, Med.Hypotheses,
vol. 51, no. 1, pp. 79-83.
Messing, E. M. & Stamey, T. A. 1978, “Interstitial cystitis: early diagnosis,
pathology, and treatment”, Urology, vol. 12, no. 4, pp. 381-392.
Nordling, J., Anjum, F. H., Bade, J. J., Bouchelouche, K., Bouchelouche, P.,
Cervigni, M., Elneil, S., Fall, M., Hald, T., Hanus, T., Hedlund, H.,
Hohlbrugger, G., Horn, T., Larsen, S., Leppilahti, M., Mortensen, S.,
Nagendra, M., Oliveira, P. D., Osborne, J., Riedl, C., Sairanen, J., Tinzl, M.,
& Wyndaele, J. J. 2004, “Primary evaluation of patients suspected of having
interstitial cystitis (IC)”, Eur.Urol., vol. 45, no. 5, pp. 662-669.
Oravisto, K. J. 1975, “Epidemiology of interstitial cystitis”, Ann.Chir
Gynaecol.Fenn., vol. 64, no. 2, pp. 75-77.
REFERENCES
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
Abdel-Mageed, A. B. 2003, “NF-kappaB-dependent gene expression of proinflammatory cytokines in T24 cells: possible role in interstitial cystitis”,
Urol.Res., vol. 31, no. 5, pp. 300-305.
Abdel-Mageed, A. B. & Ghoniem, G. M. 1998, “Potential role of rel/nuclear
factor-kappaB in the pathogenesis of interstitial cystitis”, J Urol., vol. 160,
no. 6 Pt 1, pp. 2000-2003.
Abelli, L., Conte, B., Somma, V., & et al. 1991, “Mechanical irritation induces
neurogenic inflammation in the rat urethra”, Journal of Urology, vol. 146,
pp. 1624-1626.
Aboseif, S., Tamaddon, K., Vhalfin, S., Freedman, S., & Kaptein, J. 2002,
“Sacral neuromodulation as an effective treatment for refractory pelvic
floor dysfunction”, Urology, vol. 60, no. 1, pp. 52-56.
Abraham, S. N. & Malaviya, R. 1997, “Mast cells in infection and immunity”,
Infection and Immunity, vol. 65, pp. 3501-3508.
Abramov, Y., Goldberg, R. P., McGuire, M., Golden, B., Gandhi, S., & Sand, P.
K. 2004, “Eosinophilic cystitis after bladder instillation with dimethyl sulfoxide”, Urology, vol. 63, no. 6, pp. 1182-1183.
Abrams, P. H., Cardozo, L., Fall, M., Griffiths, D., Rosier, P., Ulmsten, U., Van
Kerrebroeck, P. E. V., & Wein, A. J. 2002, “The standardisation of terminology of lower urinary tract function: report from the standardisation subcommittee of the international continence society”, Neurourology and
Urodynamics, vol. 21, pp. 167-178.
Abrams, P. H., Hanno, P., & Wein, A. J. 2005, “Overactive bladder and painful
bladder syndrome: there need not be confusion”, Neurourol Urodyn, vol.
24, pp. 149-150.
Adeyoju, A. B., Thornhill, J., Lynch, T., Grainger, R., McDermott, T., & Butler,
M. R. 1996, “The fate of the defunctioned bladder following supravesical
urinary diversion”, Br J Urol., vol. 78, no. 1, pp. 80-83.
Agarwal, M. & Dixon, R. A. 2003, “A study to detect Helicobacter pylori in
fresh and archival specimens from patients with interstitial cystitis, using
amplification methods”, BJU.Int., vol. 91, no. 9, pp. 814-816.
Ahluwalia, A., Giuliani, S., Scotland, R., & Maggi, C. A. 1998, “Ovalbumininduced neurogenic inflammation in the bladder of sensitized rats”, Br J
Pharmacol., vol. 124, no. 1, pp. 190-196.
Al Hadithi, H., Tincello, D. G., Vince, G. S., & Richmond, D. H. 2002,
“Leukocyte populations in interstitial cystitis and idiopathic reduced bladder storage”, Urology, vol. 59, no. 6, pp. 851-855.
Alagiri, M., Chottiner, S., Ratner, V., Slade, D., & Hanno, P. M. 1997,
“Interstitial cystitis: unexplained associations with other chronic disease
and pain syndromes”, Urology, vol. 49, no. 5A Suppl, pp. 52-57.
Albers, D. D. & Geyer, J. R. 1988, “Long-term
“Long-term results of cystolysis (supratrigonal denervation) of the bladder for intractable
intractable interstitial cystitis”, J Urol.,
vol. 139, no. 6, pp. 1205-1206.
Aldenborg, F., Fall, M., & Enerback, L. 1986, “Proliferation and transepithelial
migration of mucosal mast cells in interstitial cystitis”, Immunology, vol.
58, no. 3, pp. 411-416.
Aldenborg, F., Fall, M., & Enerback, L. 1989, “Mast cells in interstitial cystitis”,
Ann.Urol.(Paris), vol. 23, no. 2, pp. 165-166.
Alexacos, N., Pang, X., Boucher, W., Cochrane, D. E., Sant, G. R., &
Theoharides, T. C. 1999, “Neurotensin mediates rat bladder mast cell
degranulation triggered by acute psychological stress”, Urology, vol. 53, no.
5, pp. 1035-1040.
Anderson, J., Carrion, R., Ordorica, R., Hoffman, M., Arango, H., & Lockhart,
J. L. 1998, “Anterior enterocele following cystectomy for intractable interstitial cystitis”, J Urol., vol. 159, no. 6, pp. 1868-1870.
Anderson, J. B., Parivar, F., Lee, G., Wallington, T. B., MacIver, A. G.,
Bradbrook, R. A., & Gingell, J. C. 1989, “The enigma of interstitial cystitis-an autoimmune disease?”, Br J Urol., vol. 63, no. 1, pp. 58-63.
Anderstrom, C. R., Fall, M., & Johansson, S. L. 1989, “Scanning electron
microscopic findings in interstitial cystitis”, Br J Urol., vol. 63, no. 3, pp.
270-275.
Anonymous 1998, “Drugs for Pain”, Medical Letter, vol. 40, pp. 79-84.
Atug, F., Turkeri, L., Atug, O., & Cal, C. 2004, “Detection of Helicobacter
pylori in bladder biopsy specimens of patients with interstitial cystitis by
polymerase chain reaction”, Urol.Res., vol. 32, no. 5, pp. 346-349.
Aubert, J., Dore, B., & Touchard, G. 1983, “[Eosinophilic cystitis]”, J
Urol.(Paris), vol. 89, no. 1, pp. 65-70.
Awad, S. A., MacDiarmid, S., Gajewski, J. B., & Gupta, R. 1992, “Idiopathic
reduced bladder storage versus interstitial cystitis”, J Urol., vol. 148, no. 5,
pp. 1409-1412.
Azadzoi, K. M., T, T., Kozlowski, R., Krane, R. J., & Siroky, M. B. 1999,
“Overactivity and structural changes inthe chronically ischemic bladder”,
Journal of Urology, vol. 162, pp. 1768-1778.
Backonja, M., Beydoun, A., Edwards, K. R., Schwartz, S. L., & et.al. 1998,
“Gabapentin for the symptomatic treatment of painful neuropathy in
patients with diabetes mellitus”, JAMA, vol. 280, pp. 1831-1836.
Bade, J. J., Hollants, F., Gerkens, F., Eckhardt, M., & et.al. 2000, “The efficacy
of intravesical oxybutynin and pentosanpolysulfate in the treatment of
interstitial cystitis: a prospective, double-blind trial”, Journal of Urology,
vol. 163S, p. 60.
Bade, J. J., Laseur, M., Nieuwenburg, A., van der Weele, L. T., & Mensink, H. J.
1997, “A placebo-controlled study of intravesical pentosanpolysulphate for
the treatment of interstitial cystitis”, Br J Urol., vol. 79, no. 2, pp. 168-171.
Bade, J. J., Marrink, J., Karrenbeld, A., van der, W. L., & Mensink, H. J. 1996,
“Increased urinary levels of Tamm-Horsfall glycoprotein suggest a systemic
etiology of interstitial cystitis”, J Urol., vol. 156, no. 3, pp. 943-946.
Bade, J. J., Peeters, J. M., & Mensink, H. J. 1997, “Is the diet of patients with
interstitial cystitis related to their disease?”, Eur.Urol., vol. 32, no. 2, pp. 179183.
Bade, J. J., Rijcken, B., & Mensink, H. J. 1995, “Interstitial cystitis in The
Netherlands: prevalence, diagnostic criteria and therapeutic preferences”, J
Urol., vol. 154, no. 6, pp. 2035-2037.
Badenoch, A. W. 1971, “Chronic interstitial cystitis”, Br J Urol., vol. 43, no. 6,
pp. 718-721.
Baldessarini, R. J. 1985, “Drugs and the treatment of psychiatric disorders,” in
The Pharmacological Basis of Therapeutics, 7th edn, A. G. Gilman et al.,
eds., Macmillan Publishing Company, New York, pp. 387-445.
Barbalias, G. A., Liatsikos, E. N., Athanasopoulos, A., & Nikiforidis, G. 2000,
“Interstitial cystitis: bladder training with intravesical oxybutynin”, J Urol.,
vol. 163, no. 6, pp. 1818-1822.
Barbanti, G., Maggi, C. A., Beneforti, P., & et al. 1993, “Relief of pain following intravesical capsaicin in patients with hypersensitive disorders of the
lower urinary tract”, Br J Urol, vol. 71, pp. 686-691.
Barker, S. B., Matthews, P. N., Philip, P. F., & et.al. 1987, “Prospective study of
intravesical dimethyl sulfoxide in the treatment of chronic inflammatory
bladder disease”, Br J Urol, vol. 59, pp. 142-144.
Baron, R. 2000, “Peripheral neuropathic pain: from mechanisms to symptoms”, Clin J Pain, vol. 16, pp. 12-20.
Barrett, D. M. & Wein, A. J. 1987, “Voiding dysfunction: Diagnosis, classification, and management,” in Adult and Pediatric Urology, J. Y. Gillenwater et
al., eds., Year Book Medical Publishers, Chicago, pp. 863-892.
Barrington, J. W. & Stephenson, T. P. 1997, “Pentosanpolysulphate for interstitial cystitis”, Int.Urogynecol.J Pelvic.Floor.Dysfunct., vol. 8, no. 5, pp.
293-295.
Baskin, L. S. & Tanagho, E. A. 1992, “Pelvic pain without pelvic organs”, J
Urol., vol. 147, no. 3, pp. 683-686.
Batra, A. K. & Hanno, P. M. 1997, “Interstitial cystitis in association with scleroderma”, Indian Journal of Urology, vol. 13, p. 93.
Baykara, M., Erdogru, T., Gulkesen, K. H., Sargin, C. F., Savas, M., & Ates, M.
2003, “Does interstitial cystitis urine include possible factors effecting the
nociceptive system of the spinal cord?”, Urol.Int., vol. 71, no. 1, pp. 66-72.
Beier-Holgersen, R., Hermann, G. G., Mortensen, S. O., & Steven, K. 1994,
“The in vitro cytotoxicity of urine from patients with interstitial cystitis”, J
Urol., vol. 151, no. 1, pp. 206-207.
Bejany, D. E. & Politano, V. A. 1995, “Ileocolic neobladder in the woman with
interstitial cystitis and a small contracted bladder”, J Urol., vol. 153, no. 1,
pp. 42-43.
Bennett, R. M. 1999, “Emerging concepts in the neurobiology of chronic pain:
evidence of abnormal sensory processing in fibromyalgia”, Myo Clin Proc,
vol. 74, pp. 385-398.
Benson, H. & Epstein, M. D. 1976, “The placebo effect”, JAMA, vol. 232, pp.
1225-1226.
Benson, H. & Friedman, R. 1996, “Harnessing the power of the placebo effect
and renaming it “remembered wellness"”, Ann Rev Med, vol. 47, pp. 193199.
Berger, R. E., Miller, J. E., Rothman, I., Krieger, J. N., & Muller, C. H. 1998,
“Bladder petechiae after cystoscopy and hydrodistension in men diagnosed
with prostate pain”, J Urol., vol. 159, no. 1, pp. 83-85.
Bernardini, P., Bondavalli, C., Luciano, M., Schiavon, L., Dall'Oglio, B., Parma,
P., & Parma, A. 1999, “[Interstitial cystitis: epidemiology]”, Arch.Ital.
Urol.Androl, vol. 71, no. 5, pp. 313-315.
Bhone, A. W., Hodson, J. M., Rebuck, J. W., & et al. 1962, “An abnormal leukocyte response in interstitial cystitis”, Journal of Urology, pp. 387-391.
AL
Parsons, J. K. & Parsons, C. L. 2004, “The historical origins of interstitial cystitis”, J Urol., vol. 171, no. 1, pp. 20-22.
Pool, T. L. 1967, “Interstitial cystitis: clinical considerations and treatment”,
Clin.Obstet.Gynecol., vol. 10, no. 1, pp. 185-191.
43
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
trations in cats with interstitial cystitis”, Urology, vol. 57, no. 6 Suppl 1, p.
102.
Bullock, A. D., Becich, M. J., Klutke, C. G., & Ratliff, T. L. 1992, “Experimental
autoimmune cystitis: a potential murine model for ulcerative interstitial
cystitis”, J.Urol., vol. 148, no. 6, pp. 1951-1956.
Bumpus, H. C. 1930, “Interstitial cystitis: its treatment by overdistention of
the bladder”, Med Cl N A, vol. 13, pp. 1495-1498.
Bunyaratavej, P., La ornual, S., Kongkanand, A., Prasopsanti, K., &
Vajarapongse, R. 1993, “Ten years' experience with enterocystoplasty”, J
Med Assoc Thai., vol. 76, no. 6, pp. 327-333.
Burford, e. H. & Burford, C. E. 1958, “Hunner ulcer of the bladder: A report
of 187 cases”, Journal of Urology, vol. 79, pp. 952-955.
Burgio, K. L., Engel, B. T., & Locher, J. L. 1991, “Normative patterns of diurnal urination across 6 age decades”, Journal of Urology, vol. 145, pp. 728731.
Burkhard, F. C., Blick, N., Hochreiter, W. W., & Studer, U. E. 2004, “Urinary
urgency and frequency, and chronic urethral and/or pelvic pain in females.
Can doxycycline help?”, J.Urol., vol. 172, no. 1, pp. 232-235.
Burnstock, G. 1999, “Release of vasoactive substances from endothelial cells
by shear stress and purinergic mechanosensory transduction”, J Anat, vol.
194, p. 335.
Bushman, W., Goolsby, C., Grayhack, J. T., & Schaeffer, A. J. 1994, “Abnormal
flow cytometry profiles in patients with interstitial cystitis”, J Urol., vol. 152,
no. 6 Pt 2, pp. 2262-2266.
Byrne, D. S., Sedor, J. F., Estojak, J., Fitzpatrick, K. J., Chiura, A. N., &
Mulholland, S. G. 1999, “The urinary glycoprotein GP51 as a clinical marker for interstitial cystitis”, J Urol., vol. 161, no. 6, pp. 1786-1790.
Carlson, K., Rome, S., & Nitti, V. 2001, “Dysfunctional voiding in women”,
J.Urol, vol. 165, pp. 143-148.
Caulfield, J., Phillips, R., & Steinhardt, G. 1995, “Intravesical heparin instillation: Is there systemic absorption?”, Journal of Urology, vol. 153, p. 289A.
Chai, T. C. 2002, “Diagnosis of the painful bladder syndrome: current
approaches to diagnosis”, Clin.Obstet.Gynecol., vol. 45, no. 1, pp. 250-258.
Chai, T. C., Zhang, C., Warren, J. W., & Keay, S. 2000a, “Percutaneous sacral
third nerve root neurostimulation improves symptoms and normalizes urinary HB-EGF levels and antiproliferative activity in patients with interstitial cystitis”, Urology, vol. 55, no. 5, pp. 643-646.
Chai, T. C., Zhang, C. O., Shoenfelt, J. L., Johnson, H. W., Jr., Warren, J. W., &
Keay, S. 2000b, “Bladder stretch alters urinary heparin-binding epidermal
growth factor and antiproliferative factor in patients with interstitial cystitis”, J Urol., vol. 163, no. 5, pp. 1440-1444.
Chaiken, D. C., Blaivas, J. G., & Blaivas, S. T. 1993, “Behavioral therapy for the
treatment of refractory interstitial cystitis”, J Urol., vol. 149, no. 6, pp. 14451448.
Chambers, G. K., Fenster, H. N., Cripps, S., Jens, M., & Taylor, D. 1999, “An
assessment of the use of intravesical potassium in the diagnosis of interstitial cystitis”, J Urol., vol. 162, no. 3 Pt 1, pp. 699-701.
Chancellor, M. B. & de Groat, W. C. 1999, “Intravesical capsaicin and resiniferatoxin therapy: spicing up the ways to treat the overactive bladder”, Journal
of Urology, vol. 162, pp. 3-11.
Chancellor, M. B., Shenot, P. J., Rivas, D. A., Mandel, S., & Schwartzman, R. J.
1996, “Urological symptomatology in patients with reflex sympathetic dystrophy”, Journal of Urology, vol. 155, pp. 634-637.
Chancellor, M. B. & Yoshimura, N. 2004, “Treatment of interstitial cystitis”,
Urology, vol. 63, no. 3 Suppl 1, pp. 85-92.
Chang, P. L. 1988, “Urodynamic studies in acupuncture for women with frequency, urgency, and dysuria”, Journal of Urology, vol. 140, pp. 563-566.
Charlton, C. A. C. 1986, “Historical review: Confusions in definition,” in
Sensory Disorders of the Bladder and Urethra, N. J. R. George & J. A.
Goslling, eds., Springer-Verlag, Berlin, pp. 81-83.
Chelsky, M. J., Rosen, S. I., Knight, L. C., Maurer, A. H., Hanno, P. M., &
Ruggieri, M. R. 1994, “Bladder permeability in interstitial cystitis is similar
to that of normal volunteers: direct measurement by transvesical absorption of 99mtechnetium-diethylenetriaminepentaacetic acid”, J Urol., vol.
151, no. 2, pp. 346-349.
Chen, G.-D., Lin, L.-Y., & Gardner, J. D. 1997, “The results of laparoscopic
adhesiolysis for intractable urinary frequency”, Journal of Urology, vol. 158,
pp. 1714-1716.
Cheng, C. & Whitfield, H. N. 1990, “Cystoplasty: tubularization or detubularization”, British Journal of Urology, vol. 66, pp. 30-34.
Chesa, P. N., Armas, M. J., Artiles Hernandez, J. L., Martin, B. D., Garcia, S. C.,
Jimenez, G. C., & Betancort, d. L. 2001, “[Enterocystoplasty in the treatment of interstitial cystitis]”, Actas Urol.Esp., vol. 25, no. 7, pp. 489-492.
Christensen, M. M., Keith, I., Rhodes, P. R., & et al. 1990, “A guinea pig model
AL
Biggers, R. D. 1986, “Self-administration of dimethyl sulfoxide (DMSO) for
interstitial cystitis”, Urology, vol. 28, no. 1, pp. 10-11.
Birder, L. A., Kanai, A. J., & de Groat, W. C. 1997, “DMSO: effect on bladder
afferent neurons and nitric oxide release”, J Urol., vol. 158, no. 5, pp. 19891995.
Birder, L. A., Wolf-Johnston, A., Buffington, C. A., Roppolo, J. R., de Groat, W.
C., & Kanai, A. J. 2005, “Altered inducible nitric oxide synthase expression
and ntric oxide production in the bladder of cats with feline interstitial cystitis”, J Urol, vol. 173, pp. 625-629.
Bjorling, D. E., Jerde, T. J., Zine, M. J., Busser, B. W., Saban, M. R., & Saban, R.
1999, “Mast cells mediate the severity of experimental cystitis in mice”,
Journal of Urology, vol. 162, pp. 231-236.
Bjorling, D. E. & Wang, Z. Y. 2001, “Estrogen and neuroinflammation”,
Urology, vol. 57, no. 6 Suppl 1, pp. 40-46.
Blackford, H. N., Murray, K., Stephenson, T. P., & et.al. 1984, “Results of transvesical infiltration of the pelvic plexuses with phenol in 116 patients”, Br J
Urol, vol. 56, pp. 647-649.
Blaivas, J. G., Weiss, J. P., Desai, P., Flisser, A., Stember, D., & Stahl, P. 2005,
“Long-term follow-up of augmentation enterocystoplasty and continent
diversion in patients with benign disease”, J Urol, vol. 173, pp. 1631-1634.
Bodden-Heidrich, R. 2004, “[Psychosomatic aspects of urogynaecology:
model considerations on the pathogenesis, diagnosis and therapy]”,
Zentralbl.Gynakol., vol. 126, no. 4, pp. 237-243.
Bodner, D. R. 1988, “The urethral syndrome”, Urol Clin North Am, vol. 15, pp.
699-04.
Bouchelouche, K., Kristensen, B., Nordling, J., Horn, T., Larsen, S., Hald, T., &
Bouchelouche, P. 2001a, “Increased urinary excretion of leukotriene e (4)
in patients with interstitial cystitis”, Urology, vol. 57, no. 6 Suppl 1, p. 128.
Bouchelouche, K., Nordling, J., Hald, T., & Bouchelouche, P. 2001b,
“Treatment of interstitial cystitis with montelukast, a leukotriene d (4)
receptor antagonist”, Urology, vol. 57, no. 6 Suppl 1, p. 118.
Boucher, W., El Mansoury, M., Pang, X., Sant, G. R., & Theoharides, T. C.
1995, “Elevated mast cell tryptase in the urine of patients with interstitial
cystitis”, Br J Urol., vol. 76, no. 1, pp. 94-100.
Bourque, J. P. 1951, “Surgical management of the painful bladder”, Journal of
Urology, vol. 65, pp. 25-34.
Boye, E., Morse, M., Huttner, I., Erlanger, B. F., MacKinnon, K. J., & Klassen,
J. 1979, “Immune complex-mediated interstitial cystitis as a major manifestation of systemic lupus erythematosus”, Clin.Immunol.Immunopathol., vol. 13, no. 1, pp. 67-76.
Bracis, R., Sanders, C. V., & Gilbert, D. N. 1977, “Methicillin hemorrhagic cystitis”, Antimicrob Agents Chemother, vol. 12, pp. 438-439.
Bramble, F. J. & Morley, R. 1997, “Drug-induced cystitis: the need for vigilance”, British Journal of Urology, vol. 79, pp. 3-7.
Breau, R. H., McGrath, P. J., & Norman, R. W. 2003, “Assessing self-help issues
for patients with prostate cancer, interstitial cystitis, erectile dysfunction
and urinary diversion”, BJU.Int., vol. 92, no. 7, pp. 736-740.
Brookoff, D. 1997, “The causes and treatment of pain in interstitial cystitis,”
in Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia, pp.
177-192.
Buffington, C. A. 2004, “Comorbidity of interstitial cystitis with other unexplained clinical conditions”, J.Urol, vol. 172, no. 4 Pt 1, pp. 1242-1248.
Buffington, C. A. 1994, “Lower urinary tract disease in cats--new problems,
new paradigms”, J Nutr., vol. 124, no. 12 Suppl, pp. 2643S-2651S.
Buffington, C. A., Chew, D. J., & DiBartola, S. P. 1999, “On the definition of
feline interstitial cystitis”, J Am.Vet.Med Assoc, vol. 215, no. 2, pp. 186-188.
Buffington, C. A. & Pacak, K. 2001a, “Increased plasma norepinephrine concentration in cats with interstitial cystitis”, J Urol., vol. 165, no. 6 Pt 1, pp.
2051-2054.
Buffington, C. A., Teng, B., & Somogyi, G. T. 2002, “Norepinephrine content
and adrenoceptor function in the bladder of cats with feline interstitial cystitis”, J Urol., vol. 167, no. 4, pp. 1876-1880.
Buffington, C. A. & Woodworth, B. E. 1997, “Excretion of fluorescein in the
urine of women with interstitial cystitis”, J Urol., vol. 158, no. 3 Pt 1, pp.
786-789.
Buffington, C. A. T., Blaisdell, J. L., Binns, S. P., & et al. 1996, “Decreased urine
glycosaminoglycan excretion in cats with idiopathic cystitis”, Journal of
Urology, vol. 155, pp. 1801-1804.
Buffington, C. A. T. & Wolfe, S. A. 1998, “High affinity binding sites for
3Hsubstance P in urinary bladders of cats with interstitial cystitis”, Journal
of Urology, vol. 160, pp. 605-611.
Buffington, C. 2002, “External and internal influences on disease risk in cats”,
J Am Vet Med Assoc, vol. 220, p. 994.
Buffington, T. & Pacak, K. 2001b, “Increased plasma norepinephrine concen-
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
SECTION III
44
AL
0.9% NaCl versus 0.2 M Kcl, for the diagnosis of interstitial cystitis: a
prospective controlled study”, J Urol., vol. 170, no. 3, pp. 807-809.
Daneshgari, F., Zimmern, P. E., & Jacomides, L. 1999, “Magnetic resonance
imaging detection of symptomatic noncommunicating intraurethral wall
diverticula in women”, Journal of Urology, vol. 161, pp. 1259-1262.
Dasgupta, P., Sharma, S. D., Womack, C., Blackford, H. N., & Dennis, P. 2001,
“Cimetidine in painful bladder syndrome: a histopathological study”,
BJU.Int., vol. 88, no. 3, pp. 183-186.
Davidson, A. & Diamond, B. 2001, “Autoimmune diseases”, New England
Journal of Medicine, vol. 345, no. 5, pp. 340-350.
Davidsson, T., Carlen, B., Bak-Jensen, E., Willen, R., & Mansson, W. 1996,
“Morphologic changes in intestinal mucosa with urinary contact - effects
of urine or disuse”, Journal of Urology, vol. 156, pp. 226-232.
de la Serna, A. R. & Alarcon-Segovia, D. 1981, “Chronic interstitial cystitis as
an initial major manifestation of systemic lupus erythematosus”, J
Rheumatol., vol. 8, no. 5, pp. 808-810.
Dees, J. E. 1953, “The use of cortisone in interstitial cystitis: a preliminary
report”, J Urol., vol. 69, no. 4, pp. 496-502.
DeJuana, C. P. & Everett, J. C., Jr. 1977, “Interstitial cystitis: experience and
review of recent literature”, Urology, vol. 10, no. 4, pp. 325-329.
Denson, M. A., Griebling, T. L., Cohen, M. B., & Kreder, K. J. 2000,
“Comparison of cystoscopic and histological findings in patients with suspected interstitial cystitis”, J Urol., vol. 164, no. 6, pp. 1908-1911.
Dimitrakov, J., Tchitalov, J., Zlatanov, T., Dikov, D., & Rawadi, G. 2001,
“Corticotropin-releasing hormone pert
perturbations in interstitial cystitis
patients: evidence for abnormal sympathetic activity”, Urology, vol. 57, no.
6 Suppl 1, p. 128.
Dimitrakov, J. D. 2001, “A case of familial clustering of interstitial cystitis and
chronic pelvic pain syndrome”, Urology, vol. 58, no. 2, p. 281.
Dimitriadou, V., Buzzi, M. G., Moskowitz, M. A., & et al. 1991, “Trigeminal
sensory fiber stimulation induces morphological changes reflecting secretion in rat dura mater mast cells”, Neuroscience, vol. 44, pp. 97-112.
Dimitriadou, V., Buzzi, M. G., Theoharides, T. C., & et al. 1992,
“Ultrastructural evidence for neurogenically mediated changes in blood
vessels of the rat dura mater and tongue following antidromic trigeminal
stimulation”, Neuroscience, vol. 48, pp. 187-203.
Dixon, J. S., Holm-Bentzen, M., Gilpin, C. J., Gosling, J. A., Bostofte, E., Hald,
T., & Larsen, S. 1986, “Electron microscopic investigation of the bladder
urothelium and glycocalyx in patients with interstitial cystitis”, J Urol., vol.
135, no. 3, pp. 621-625.
Dodson, A. I. 1926, “Hunner's ulcer of the bladder; a report of ten cases”, Va
Med Mon, vol. 53, pp. 305-310.
Doggweiler, R., Jasmin, L., & Schmidt, R. A. 1998, “Neurogenically mediated
cystitis in rats: an animal model”, Journal of Urology, vol. 160, pp. 15511556.
Doggweiler-Wiygul, R., Blankenship, J., & MacDiarmid, S. A. 2001, “Review
on chronic pelvic pain from a urological point of view”, World J Urol., vol.
19, no. 3, pp. 160-165.
Doggweiler-Wiygul, R. & Wiygul, J. P. 2002, “Interstitial cystitis, pelvic pain,
and the relationship to myofascial pain and dysfunction: a report on four
patients”, World J Urol., vol. 20, no. 5, pp. 310-314.
Doi, K., Saito, Y., Nikai, T., Morimoto, N., Nakatani, T., & Sakura, S. 2001,
“Lumbar sympathetic block for pain relief in two patients with interstitial
cystitis”, Reg Anesth.Pain Med, vol. 26, no. 3, pp. 271-273.
Domingue, G. J. & Ghoniem, G. M. 1997, “Occult infection in interstitial cystitis,” in Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia,
pp. 77-86.
Domingue, G. J., Ghoniem, G. M., Bost, K. L., Fermin, C., & Human, L. G.
1995, “Dormant microbes in interstitial cystitis”, J Urol., vol. 153, no. 4, pp.
1321-1326.
Dondore, P. A., Schwartz, A. M., & Semerjian, H. 1996, “Mast cell counts are
not useful in the diagnosis of nonulcerative interstitial cystitis”, Journal of
Urology, vol. 155, pp. 885-887.
DuBeau, C., Khullar, V., & Versi, E. 2005, “"Unblinding” in randomized controlled drug trials for urinary incontinence: implications for assessing outcomes when adverse effects are evident”, Neurourol Urodyn, no. 13-20.
Duldulao, K. E., Diokno, A. C., & Mitchell, B. 1997, “Value of urinary cytology in women presenting with urge incontinence and/or irritative voiding
symptoms”, Journal of Urology, vol. 157, pp. 113-116.
Duncan, J. L. & Schaeffer, A. J. 1997, “Do infectious agents cause interstitial
cystitis?”, Urology, vol. 49, no. 5A Suppl, pp. 48-51.
Dundore, P. A., Schwartz, A. M., & Semerjian, H. 1996, “Mast cell counts are
not useful in the diagnosis of nonulcerative interstitial cystitis”, J Urol., vol.
155, no. 3, pp. 885-887.
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
for study of bladder mast cell function: Histamine release and smooth
muscle contraction”, Journal of Urology, vol. 144, pp. 1293-1300.
Christmas, T. J. 1997, “Historical aspects of interstitial cystitis,” in Interstitial
Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia, pp. 1-8.
Christmas, T. J. 1994, “Lymphocyte sub-populations in the bladder wall in
normal bladder, bacterial cystitis and interstitial cystitis”, Br J Urol., vol. 73,
no. 5, pp. 508-515.
Christmas, T. J., Holmes, S. A., & Hendry, W. F. 1996, “Bladder replacement by
ileocystoplasty: the final treatment for interstitial cystitis”, Br J Urol., vol.
78, no. 1, pp. 69-73.
Christmas, T. J. & Rode, J. 1991, “Characteristics of mast cells in normal bladder, bacterial cystitis and interstitial cystitis”, Br J Urol., vol. 68, no. 5, pp.
473-478.
Christmas, T. J., Rode, J., Chapple, C. R., Milroy, E. J., & Turner-Warwick, R.
T. 1990, “Nerve fibre proliferation in interstitial cystitis”, Virchows Arch.A
Pathol.Anat.Histopathol., vol. 416, no. 5, pp. 447-451.
Christmas, T. J., Smith, G. L., & Rode, J. 1996, “Detrusor myopathy: an accurate predictor of bladder hypocompliance and contracture in interstitial
cystitis”, Br J Urol., vol. 78, no. 6, pp. 862-865.
Chuang, Y. C., Yoshimura, N., Huang, C. C., Chiang, P. H., & Chancellor, M.
B. 2004, “Intravesical botulinum toxin a administration produces analgesia
against acetic acid induced bladder pain responses in rats”, J.Urol., vol. 172,
no. 4 Pt 1, pp. 1529-1532.
Chudwin, D. S., Chesney, P. J., Mischler, E. H., & et al. 1979, “Hematuria associated with carbenicillin and other semisynthetic penicillins (letter)”, Am J
Dis Child, vol. 133, pp. 98-99.
Chung, M. K. 2004, “Interstitial cystitis in persistent posthysterectomy chronic pelvic pain”, JSLS., vol. 8, no. 4, pp. 329-333.
Clauw, D. J., Schmidt, M., Radulovic, D., Singer, A., Katz, P., & Bresette, J. 1997,
“The relationship between fibromyalgia and interstitial cystitis”, J
Psychiatr.Res., vol. 31, no. 1, pp. 125-131.
Clemens, J., Meenan, R., Rosetti, M., & Calhoun, E. 2005, “Prevalence and
incidence of interstitial cystitis in a managed care population”, J Urol, vol.
173, pp. 98-102.
Clemmensen, O. J., Lose, G., Holm-Bentzen, M., & Colstrup, H. 1988, “Skin
reactions to urine in patients with interstitial
stitial cystitis”, Urology, vol. 32, no.
1, pp. 17-20.
Close, C. E., Carr, M. C., Burns, M. W., Miller, J. L., Bavendam, T. G., Mayo,
M. E., & Mitchell, M. E. 1996, “Interstitial cystitis in children”, J Urol., vol.
156, no. 2 Pt 2, pp. 860-862.
Collan, Y., Alfthan, O., Kivilaakso, E., & Oravisto, K. J. 1976, “Electron microscopic and histological findings on urinary bladder epithelium in interstitial cystitis”, Eur.Urol., vol. 2, no. 5, pp. 242-247.
Collas, D. M. & Malone-Lee, J. G. 1996, “Age-associated changes in detrusor
sensory function in women with lower urinary tract symptoms”, Int
Urogynecol J, vol. 7, pp. 24-29.
Comiter, C. V. 2003, “Sacral neuromodulation for the symptomatic treatment
of refractory interstitial cystitis: a prospective
prospective study”, J Urol., vol. 169, no. 4,
pp. 1369-1373.
Consensus document 1993, “Consensus document on fibromyalgia: The
Copenhagen declaration”, J Musculoskeletal Pain, vol. 1, pp. 295-312.
Cook, F. V., Farrar, W. E., & Kreutner, A. 1979, “Hemorrhagic cystitis and
ureteritis, and interstitial nephritis associated with administration of penicillin G”, Journal of Urology, vol. 122, pp. 110-111.
Cornish, J., Nickel, J. C., Vanderwee, M., & et al. 1990, “Ultrastructural visualization of human bladder mucus”, Urol Res, vol. 18, pp. 263-264.
Costello, A. J., Crowe, H., & Agarwal, D. 2000, “Supratrigonal cystectomy and
ileocystoplasty in management of interstitial cystitis”, Aust.N.Z.J Surg., vol.
70, no. 1, pp. 34-38.
Creighton, S. M., Pearce, J. M., Robson, I., Wang, K., & Stanton, S. L. 1991,
“Sensory urgency: how full is your bladder?”, British Journal of Obstetrics
and Gynaecology, vol. 98, pp. 1287-1289.
Cross, S. 1994, “Pathophysiology of Pain”, Mayo Clin Proc, vol. 69, pp. 375383.
Cruz, F., Guimaraes, M., Silva, C., Rio, M. E., Coimbra, A., & Reis, M. 1997,
“Desensitization of bladder sensory fibers by intravesical capsaicin has long
lasting clinical and urodynamic effects in patients with hyperactive or
hypersensitive bladder dysfunction”, Journal of Urology, vol. 157, pp. 585589.
Curhan, G. C., Speizer, F. E., Hunter, D. J., Curhan, S. G., & Stampfer, M. J.
1999, “Epidemiology of interstitial cystitis: a population based study”, J
Urol., vol. 161, no. 2, pp. 549-552.
Daha, L. K., Riedl, C. R., Hohlbrugger, G., Knoll, M., Engelhardt, P. F., &
Pfluger, H. 2003, “Comparative assessment of maximal bladder capacity,
45
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
tectin (MUC-1 glycoprotein) in the menstrual cycle and interstitial cystitis”, J Urol., vol. 156, no. 3, pp. 938-942.
Erickson, D. R., Morgan, K. C., Ordille, S., Keay, S. K., & Xie, S. X. 2001,
“Nonbladder related symptoms in patients with interstitial cystitis”, J Urol.,
vol. 166, no. 2, pp. 557-561.
Erickson, D. R., Ordille, S., Martin, A., & Bhavanandan, V. P. 1997, “Urinary
chondroitin sulfates, heparan sulfate and total sulfated glycosaminoglycans
in interstitial cystitis”, J Urol., vol. 157, no. 1, pp. 61-64.
Erickson, D. R., Sheykhnazari, M., Ordille, S., & Bhavanandan, V. P. 1998,
“Increased urinary hyaluronic acid and interstitial cystitis”, J Urol., vol. 160,
no. 4, pp. 1282-1284.
Erickson, D. R., Xie, S. X., Bhavanandan, V. P., Wheeler, M. a., Hurst, R. E.,
Demers, L. M., Kushner, L., & Keay, S. K. 2002, “A comparison of multiple
urine markers for interstitial cystitis”, J Urol., vol. 167, no. 6, pp. 2461-2469.
Erickson, DR., Tomaszewski, J. E., Kunselman, A. R., Bentley, C. M., Peters, K.
M., Rovner, E. S., Demers, L. M., Wheeler, M., & Keay, S. K. 2005, “Do the
national institute of diabetes and digestive and kidney diseases cystoscopic
criteria associate with other clinical and objective features of interstitial
cystitis?”, J Urol, vol. 173, pp. 93-97.
Everaert, K., Devulder, J., De Muynck, M., Stockman, S., Depaepe, H., De
Looze, D., Van Butyen, J., & Oosterlinck, W. 2001, “The pain cycle: implications for the diagnosis and treatment of pelvic pain syndromes”,
International Urogynecology Journal, vol. 12, no. 1, pp. 9-14.
Ezzo, J., Berman, B., Hadhazy, V., Jadad, A., Lao, L., & Singh, B. 2000, “Is
acupuncture effective for the treatment of chronic pain? A systematic
review”, Pain, vol. 86, pp. 217-225.
Fall, M. 1987, “Transcutaneous electrical nerve stimulation in interstitial cystitis. Update on clinical experience”, Urology, vol. 29, no. 4 Suppl, pp. 40-42.
Fall, M. 1985, “Conservative management of chronic interstitial cystitis: transcutaneous electrical nerve stimulation and transurethral resection”, J
Urol., vol. 133, no. 5, pp. 774-778.
Fall, M., Carlsson, C. A., & Erlandson, B. E. 1980, “Electrical stimulation in
interstitial cystitis”, J Urol., vol. 123, no. 2, pp. 192-195.
Fall, M., Johansson, S. L., & Aldenborg, F. 1987, “Chronic interstitial cystitis: a
heterogeneous syndrome”, J Urol., vol. 137, no. 1, pp. 35-38.
Fall, M. & Lindstrom, S. 1994, “Transcutaneous electrical nerve stimulation in
classic and nonulcer interstitial cystitis”, Urol.Clin.North Am., vol. 21, no.
1, pp. 131-139.
Farkas, A., Waisman, J., & Goodwin, W. E. 1977, “Interstitial cystitis in adolescent girls”, J Urol., vol. 118, no. 5, pp. 837-839.
Felsen, D., Frye, S., Trimble, L. A., Bavendam, T. G., Parsons, C. L., Sim, Y., &
Vaughan, E. D., Jr. 1994, “Inflammatory mediator profile in urine and bladder wash fluid of patients with interstitial cystitis”, J Urol., vol. 152, no. 2 Pt
1, pp. 355-361.
Feltis, J. T., Perez-Marrero, R., & Emerson, L. E. 1987, “Increased mast cells of
the bladder in suspected cases of interstitial cystitis: a possible disease
marker”, J Urol., vol. 138, no. 1, pp. 42-43.
Filippou, A. S., Sant, G. R., & Theoharides, T. C. 1999, “Mast cell in interstitial
cystitis”, Urologia Integrada y de Investigacion, vol. 4, no. 4, pp. 315-323.
Fisher, B. P., Bavendam, T. G., Roberts, B. W., & et al. “Blinded placebo controlled evaluation on the ingestion of acidic foods and their effect on urinary pH and the symptomatology of interstitial cystitis”, NIDDK, Orlando,
Florida, p. 53.
Fister, G. M. 1938, “Similarity of interstitial cystitis (Hunner ulcer) to lupus
erythematosus”, Journal of Urology, vol. 40, pp. 37-51.
Fitzgerald, M. & Brubaker, L. 2003, “Variability of 24-hour voiding diary variables among asymptomatic women”, Journal of Urology, vol. 160, pp. 207209.
Fitzgerald, M., Butler, N., Shott, S., & Brubaker, L. 2002, “Bother arising from
urinary frequency in women”, Neurourol Urodyn, vol. 21, pp. 36-41.
Fitzpatrick, C. C., DeLancey, J. O., Elkins, T. E., & McGuire, E. J. 1993, “Vulvar
vestibulitis and interstitial cystitis: a disorder of urogenital sinus-derived
epithelium?”, Obstet.Gynecol., vol. 81, no. 5 (Pt 2), pp. 860-862.
Fleischmann, J. 1994, “Calcium channel antagonists in the treatment of interstitial cystitis”, Urol.Clin.North Am., vol. 21, no. 1, pp. 107-111.
Flood, H. D., Malhotra, S. J., O'Connell, H. E., Ritchey, M. J., Bloom, D. A., &
McGuire, E. J. 1995, “Long-term results and complications using augmentation cystoplasty in reconstructive urology”, Neurourol.Urodyn., vol. 14,
no. 4, pp. 297-309.
Foreman, J. C. 1987, “Peptides and neurogenic inflammation”, Br Med Bull,
vol. 43, pp. 386-400.
Forrest, J. B. & Schmidt, S. 2004, “Interstitial cystitis, chronic nonbacterial
prostatitis and chronic pelvic pain syndrome in men: a common and frequently identical clinical entity”, J.Urol, vol. 172, no. 6 Pt 2, pp. 2561-2562.
Forsell, T., Ruutu, M., Isoniemi, H., Ahonen, J., & Alfthan, O. 1996,
AL
Dunn, M., Ramsden, P. D., Roberts, J. B., Smith, J. C., & Smith, P. J. 1977,
“Interstitial cystitis, treated by prolonged bladder distension”, Br J Urol.,
vol. 49, no. 7, pp. 641-645.
Dupont, M., Spitsbergen, J., Kim, K., Tuttle, J., & Steers, W. 2001, “Histological
and neurotrophic changes triggered by varying models of bladder inflammation”, J Urol, vol. 166, pp. 1111-1118.
Durier, J. L. 1992, “The application of anti-anaerobic antibiotics to the treatment of female bladder dysfunctions”, Neurourol Urodyn, vol. 11, p. 418.
Edwards, L., Bucknall, T. E., & Makin, C. 1986, “Interstitial cystitis: possible
cause and clinical study of sodium cromoglycate”, Br J Urol., vol. 58, no. 1,
pp. 95-96.
Ehren, I., Hosseini, A., Herulf, M., Lundberg, J. O., & Wiklund, N. P. 1999,
“Measurement of luminal nitric oxide in bladder inflammation using a silicon balloon catheter: a novel minimally invasive method”, Urology, vol. 54,
no. 2, pp. 264-267.
Ehren, I., Lundberg, J. O., Adolfsson, J., & Wiklund, N. P. 1998, “Effects of Larginine treatment on symptoms and bladder nitric oxide levels in patients
with interstitial cystitis”, Urology, vol. 52, no. 6, pp. 1026-1029.
Eigner, E. B. & Freiha, F. S. 1990, “The fate of the remaining bladder following
supravesical diversion”, J Urol., vol. 144, no. 1, pp. 31-33.
Ek, A., Engberg, A., Frodin, L., & Jonsson, G. 1978, “The use of dimethyl-sulfoxide (DMSO) in the treatment of interstitial cystitis”, Scand.J
Urol.Nephrol., vol. 12, no. 2, pp. 129-131.
El Mansoury, M., Boucher, W., Sant, G. R., & Theoharides, T. C. 1994,
“Increased urine histamine and methylhistamine in interstitial cystitis”, J
Urol., vol. 152, no. 2 Pt 1, pp. 350-353.
Elbadawi, A. 1997, “Interstitial cystitis: a critique of current concepts with a
new proposal for pathologic diagnosis and pathogenesis”, Urology, vol. 49,
no. 5A Suppl, pp. 14-40.
Elbadawi, A. E. & Light, J. K. 1996, “Distinctive ultrastructural pathology of
nonulcerative interstitial cystitis: new observations and their potential significance in pathogenesis”, Urol.Int., vol. 56, no. 3, pp. 137-162.
Elgavish, A., Pattanaik, A., Lloyd, K., & Reed, R. 1997, “Evidence for altered
proliferative ability of progenitors of urothelial cells in interstitial cystitis”,
J Urol., vol. 158, no. 1, pp. 248-252.
Elgavish, A., Robert, B., Lloyd, K., & et al. 1995, “Evidence for a mechanism of
bacterial toxin action that may lead to the onset of urothelial injury in the
interstitial cystitis bladder (abstract)”, Journal of Urology, vol. 153, p. 329A.
Elgebaly, S. A., Allam, M. E., Walzak, M. P., Jr., Oselinsky, D., Gillies, C., &
Yamase, H. 1992, “Urinary neutrophil chemotactic factors in interstitial
cystitis patients and a rabbit model of bladder inflammation”, J Urol., vol.
147, no. 5, pp. 1382-1387.
Elzawahri, A., Bissada, N. K., Herchorn, S., boul-Enein, H., Ghoneim, M.,
Bissada, M. A., Finkbeiner, A., & Glazer, A. A. 2004, “Urinary conduit formation using a retubularized bowel from continent urinary diversion or
intestinal augmentations: ii. Does it have a role in patients with interstitial
cystitis?”, J.Urol, vol. 171, no. 4, pp. 1559-1562.
Emerson, L. E. & Feltis, J. T. 1986, “Urodynamic factors affecting response to
DMSO in the treatment of interstitial cystitis”, Journal of Urology, vol. 135,
p. 188A.
Enerback, L., Fall, M., & Aldenborg, F. 1989, “Histamine and mucosal mast
cells in interstitial cystitis”, Agents Actions, vol. 27, no. 1-2, pp. 113-116.
Engelmann, U., Burger, R., & Jacobi, G. 1982, “Experimental investigations on
the absorption of intravesically instilled mitomycin-C in the urinary bladder of the rat”, Eur Urol, vol. 8, pp. 176-181.
English, S. F., Liebert, M., Cross, C. A., & McGuire, E. J. 1998, “The incidence
of Helicobacter pylori in patients with interstitial cystitis”, J Urol., vol. 159,
no. 3, pp. 772-773.
Ercan, F., Oktay, S., & Erin, N. 2001, “Role of afferent neurons in stress
induced degenerative changes of the bladder”, J.Urol., vol. 165, pp. 235-239.
Erickson, D. R. 1999, “Interstitial cystitis: update on etiologies and therapeutic options”, J Womens Health Gend.Based.Med, vol. 8, no. 6, pp. 745-758.
Erickson, D. R. 1995, “Glomerulations in women with urethral sphincter deficiency: report of 2 cases [corrected]”, J Urol., vol. 153, no. 3 Pt 1, pp. 728729.
Erickson, D. R. 2001, “Urine markers of interstitial cystitis”, Urology, vol. 57,
no. 6 Suppl 1, pp. 15-21.
Erickson, D. R., Belchis, D. A., & Dabbs, D. J. 1997, “Inflammatory cell types
and clinical features of interstitial cystitis”, J Urol., vol. 158, no. 3 Pt 1, pp.
790-793.
Erickson, D. R., Kunselman, A. R., Bentley, C. M., Peters, K. M., Rovner, E. S.,
Demers, L. M., & Tomaszewski, J. E. 2004, “Is urine methylhistamine a useful marker for interstitial cystitis?”, J.Urol, vol. 172, no. 6, Part 1 of 2, pp.
2256-2260.
Erickson, D. R., Mast, S., Ordille, S., & Bhavanandan, V. P. 1996, “Urinary epi-
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
SECTION III
46
AL
ment of interstitial cystitis: efficacy at 6 months and 1 year”, Eur.Urol., vol.
41, no. 1, pp. 79-84.
Glenning, P. P. 1985, “Urinary voiding patterns of apparently normal women”,
Aust NZ J Obstet Gynaec, vol. 25, pp. 62-65.
Goin, J. E., Olaleye, D., Peters, K. M., Steinert, B., Habicht, K., & Wynant, G.
1998, “Psychometric analysis of the University of Wisconsin Interstitial
Cystitis Scale: implications for use in randomized clinical trials”, J Urol.,
vol. 159, no. 3, pp. 1085-1090.
Golomb, J., Klutke, C. G., Lewin, K. J., & et.al. 1989, “Bladder neoplasms associated with augmentation cystoplasty: Report of 2 cases and literature
review”, Journal of Urology, vol. 142, pp. 377-380.
Gordon, H. L., Rossen, R. D., Hersh, E. M., & Yium, J. J. 1973, “Immunologic
aspects of interstitial cystitis”, J Urol., vol. 109, no. 2, pp. 228-233.
Gordon, Z., Parsons, C. L., & Monga, M. 2003, “Intravesical ethanol test: an
ineffective measure of bladder hyperpermeability”, Urology, vol. 61, no. 3,
pp. 555-557.
Goris, A. & Jan, R. 1998, “Reflex sympathetic dystrophy: model of a severe
regional inflammatory response syndrome”, World Journal of Surgery, vol.
22, pp. 197-202.
Gourlay, G. K. 1994, “Long-term use of opiods in chronic pain patients with
nonterminal disease states”, Pain Rev, vol. 1, pp. 62-76.
Green, M., Filippou, A., Sant, G., & Theoharides, T. C. 2004, “Expression of
intercellular adhesion molecules in the bladder of patients with interstitial
cystitis”, Urology, vol. 63, no. 4, pp. 688-693.
Greenhill, J. P. 1947, “Sympathectomy and intraspinal alcohol injections for
relief of pelvic pain”, BMJ, vol. 29, pp. 859-862.
Gregoire, M., Liandier, F., Naud, A., Lacombe, L., & Fradet, Y. 2002, “Does the
potassium stimulation test predict cy
cystometric, cystoscopic outcome in
interstitial cystitis?”, J Urol., vol. 168, no. 2, pp. 556-557.
Haarala, M., Jalava, J., Laato, M., Kiilholma, P., Nurmi, M., & Alanen, A. 1996,
“Absence of bacterial DNA in the bladder of patients with interstitial cystitis”, J Urol., vol. 156, no. 5, pp. 1843-1845.
Haarala, M., Kiiholma, P., Nurmi, M., Uksila, J., & Alanen, A. 2000, “The role
of Borrelia burgdorferi in interstitial cystitis”, Eur.Urol., vol. 37, no. 4, pp.
395-399.
Hakenberg, O. & Wirth, M. 2002, “Chronic pelvic pain in men”, Urologia
Internationalis, vol. 68, pp. 138-143.
Hald, T., Barnard, R. J., & Holm-Bentzen, M. 1986, “Treatment of interstitial
cystitis,” in Sensory Disorders of the Bladder and Urethra, N. J. R. George
& J. A. Gosling, eds., Springer-Verlag, Berlin, pp. 73-78.
Hamer, A. J., Nicholson, S., & Padfield, C. J. 1992, “Spontaneous rupture of the
bladder in interstitial cystitis”, Br J Urol., vol. 69, no. 1, p. 102.
Hampson, S. J., Christmas, T. J., & Moss, M. T. 1993, “Search for mycobacteria in interstitial cystitis using mycobacteria-specific DNA probes with signal amplification by polymerase chain reaction”, Br J Urol., vol. 72, no. 3,
pp. 303-306.
Hampson, S. J. & Woodhouse, C. R. J. 1994, “Sodium pentosanpolysulphate in
the management of haemorrhagic cystitis: experience with 14 patients”, Eur
Urol, vol. 25, pp. 40-42.
Hanash, K. A. & Pool, T. L. 1970, “Interstitial and hemorrhagic cystitis: Viral,
bacterial and fungal studies”, Journal of Urology, vol. 104, pp. 705-706.
Hanash, K. A. & Pool, T. L. 1969, “Interstitial cystitis in men”, J Urol., vol. 102,
no. 4, pp. 427-428.
Hand, J. R. 1949, “Interstitial cystitis: report of 223 cases (204 women and 19
men)”, Journal of Urology, vol. 61, pp. 291-310.
Hanno, P. 2005, “Forging an international consensus: progress in painful
bladder syndrome/interstitial cystitis”, International Urogynecology, vol.
16, no. Suppl 1, pp. 2-6.
Hanno, P., Baranowski, A., Fall, M., Gajewski, J. B., Nordling, J., Nyberg, L.,
Ratner, V., Rosamilia, A., & Ueda, T. 2005, “Painful bladder syndrome
(including interstitial cystitis),” in Incontinence, 3 edn, vol. 2 P. H. Abrams,
A. J. Wein, & L. Cardozo, eds., Health Publications Limited, Paris, pp. 14561520.
Hanno, P., Levin, R. M., Monson, F. C., Teuscher, C., Zhou, Z. Z., Ruggieri, M.,
Whitmore, K., & Wein, A. J. 1990, “Diagnosis of interstitial cystitis”, J Urol.,
vol. 143, no. 2, pp. 278-281.
Hanno, P. M. 1994b, “Amitriptyline in the treatment of interstitial cystitis”,
Urol.Clin.North Am., vol. 21, no. 1, pp. 89-91.
Hanno, P. M. 1997, “Analysis of long-term Elmiron therapy for interstitial cystitis”, Urology, vol. 49, no. 5A Suppl, pp. 93-99.
Hanno, P. M. 1994a, “Diagnosis of interstitial cystitis”, Urol.Clin.North Am.,
vol. 21, no. 1, pp. 63-66.
Hanno, P. M. 1995, “Interstitial cystitis and female urethral syndrome,” in
Clinical Urologic Practice, B. S. Stein, ed., W W Norton and Company, New
York, pp. 611-622.
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
“Cyclosporine in severe interstitial cystitis”, J Urol., vol. 155, no. 5, pp. 15911593.
Foster, H. E., Smith, S., Wheeler, M., & Weiss, R. M. 1997, “Nitric oxide and
interstitial cystitis”, Advances in Urology, vol. 10, pp. 1-25.
Fowler, J. E., Jr. 1981, “Prospective study of intravesical dimethyl sulfoxide in
treatment of suspected early interstitial cystitis”, Urology, vol. 18, no. 1, pp.
21-26.
Fowler, J. E. 1989, “Nonmicrobial inflammation and noninflammatory disorders,” in Urinary Tract infection and Inflammation, J. E. Fowler, ed., Year
Book Medical Publishers, Chicago, pp. 292-293.
Fowler, J. E., Jr., Lynes, W. L., Lau, J. L., Ghosh, L., & Mounzer, A. 1988,
“Interstitial cystitis is associated with intraurothelial Tamm-Horsfall protein”, J Urol., vol. 140, no. 6, pp. 1385-1389.
Franke, J. J., Stratton, C. W., & Mitchell, W. M. 1999, “Chlamydia pneumoniae in patients with interstitial cystitis”, Journal of Urology, vol. 161, p. 29.
Frazer, M. I., Haylen, B. T., & Sissons, M. 1990, “Do women with idiopathic
sensory urgency have early interstitial cystitis?”, Br J Urol., vol. 66, no. 3, pp.
274-278.
Freedman, A. I., Wein, A. J., Whitmore, K., & et.al. 1989, “In vitro effects of
intravesical dimethyl sulfoxide”, Neurourol Urodyn, vol. 8, pp. 277-283.
Freiha, F. S., Faysal, M. H., & Stamey, T. A. 1980, “The surgical treatment of
intractable interstitial cystitis”, J Urol., vol. 123, no. 5, pp. 632-634.
Freiha, F. S. & Stamey, T. A. 1979, “Cystolysis: a procedure for the selective
denervation of the bladder”, Trans.Am.Assoc Genitourin.Surg., vol. 71, pp.
50-54.
Fritjofsson, A., Fall, M., Juhlin, R., Persson, B. E., & Ruutu, M. 1987,
“Treatment of ulcer and nonulcer interstitial cystitis with sodium pentosanpolysulfate: a multicenter trial”, J Urol., vol. 138, no. 3, pp. 508-512.
Frontz, W. A. 1922, “Discussion”, Tr Am Assn Gen-Urin Surg, vol. 15, p.
434=435.
Gajewski, J. B. & Awad, S. A. 1997, “Urodynamic evaluation in interstitial cystitis,” in Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia,
pp. 169-172.
Gallagher, D. J. A., Montgomerie, J. Z., & North, J. D. K. 1965, “Acute infections of the urinary tract and the urethral syndrome in general practice”, Br
Med J, vol. 1, pp. 622-626.
Galli, S. J. 1993, “New concepts about the mast cell”, N Engl J Med, vol. 328,
pp. 257-265.
Galloway, N. T., Gabale, D. R., & Irwin, P. P. 1991, “Interstitial cystitis or reflex
sympathetic dystrophy of the bladder?”, Semin.Urol., vol. 9, no. 2, pp. 148153.
Gambone, J., Mittman, B., Munro, M., & et.al. 2002, “Consensus statement for
the management of chronic pelvic pain and endometriosis: proceedings of
an expert-panel consensus process”, Fertility Sterility, vol. 78, pp. 961-972.
Geirsson, G., Wang, Y. H., Lindstrom, S., & Fall, M. 1993, “Traditional
acupuncture and electrical stimulation of the posterior tibial nerve. A trial
in chronic interstitial cystitis”, Scand.J Urol.Nephrol., vol. 27, no. 1, pp. 6770.
Geist, R. W. & Antolak, S. J., Jr. 1970, “Interstitial cystitis in children”, J Urol.,
vol. 104, no. 6, pp. 922-925.
George, N. J. R. 1986, “Preface,” in Sensory Disorders of the Bladder and
Urethra, N. J. R. George & J. A. Gosling, eds., Springer-Verlag, Berlin, p. vii.
Gheyi, S. K., Robertson, A., & Atkinson, P. M. 1999, “Severe interstitial cystitis
caused by tiaprofenic acid”, J R.Soc.Med, vol. 92, no. 1, p. 17.
Ghoniem, G. M., Shaaban, A. M., & Clarke, M. R. 1995, “Irritable bladder syndrome in an animal model: a continuous monitoring study”,
Neurourol.Urodyn., vol. 14, no. 6, pp. 657-665.
Gillenwater, J. Y. & Wein, A. J. 1988, “Summary of the National Institute of
Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial
Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29,
1987”, J Urol., vol. 140, no. 1, pp. 203-206.
Gillespie, L. 1994, “Destruction of the vesicoureteric plexus for the treatment
of hypersensitive bladder disorders”, Br J Urol., vol. 74, no. 1, pp. 40-43.
Gillespie, L., Bray, R., Levin, N., & Delamarter, R. 1991, “Lumbar nerve root
compression and interstitial cystitis--response to decompressive surgery”,
Br J Urol., vol. 68, no. 4, pp. 361-364.
Gilron, I., Bailey, J., Tu, D., Holden, R., Weaver, D., & Houlden, R. 2005,
“Morphine, gabapentin, or their combination for neuropathic pain”,
NEJM, vol. 352, no. 13, pp. 1324-1334.
Gittes, R. F. 2002, “Female prostatitis”, Urol Clin North Am, vol. 29, no. 3, pp.
613-616.
Gittes, R. F. & Nakamura, R. M. 1996, “Female Urethral Syndrome -- a female
prostatitis?”, Western Journal of Medicine, vol. 164, pp. 435-438.
Glemain, P., Riviere, C., Lenormand, L., Karam, G., Bouchot, O., & Buzelin, J.
M. 2002, “Prolonged hydrodistention of the bladder for symptomatic treat-
47
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
“Painful bladder disease: clinical and pathoanatomical differences in 115
patients”, J Urol., vol. 138, no. 3, pp. 500-502.
Holm-Bentzen, M., Larsen, S., Hainau, B., & et.al. 1985, “Nonobstructive
detrusor myopathy in a group of patients with chronic abacterial cystitis”,
Scand J Urol Nephrol, vol. 19, pp. 21-26.
Holm-Bentzen, M., Nordling, J., & Hald, T. 1990, “Etiology: Etiologic and
pathogenetic theories in interstitial cystitis,” in Interstitial Cystitis, P. M.
Hanno et al., eds., Springer-Verlag, London, pp. 63-77.
Holm-Bentzen, M., Sondergaard, I., & Hald, T. 1987, “Urinary excretion of a
metabolite of histamine (1,4-methyl-imidazole-acetic-acid) in painful
bladder disease”, Br J Urol., vol. 59, no. 3, pp. 230-233.
Holzberg, A., Kellog-Spadt, S., Lukban, J., & Whitmore, K. 2001, “Evaluation
of transvaginal theile massage as a therapeutic intervention for women
with interstitial cystitis”, Urology, vol. 57, no. 6 Suppl 1, p. 120.
Hooton, T. M. 1988, “Epidemiology, definitions, and terminology in urinary
tract infections,” in New Trends in Urinary Tract Infections, H. C. Neu & J.
D. Williams, eds., Karger, Basel, pp. 5-8.
Houpt, K. A. 1991, “Housesoiling: Treatment of a common feline problem”,
Vet Med, vol. 86, pp. 1000-1006.
Howard, F. M. 2003b, “The role of laparoscopy in the chronic pelvic pain
patient”, Clin.Obstet.Gynecol., vol. 46, no. 4, pp. 749-766.
Howard, F. M. 2003a, “Chronic pelvic pain”, Obstet.Gynecol., vol. 101, no. 3,
pp. 594-611.
Hughes, O. D., Kynaston, H. G., Jenkins, B. J., Stephenson, T. P., & Vaughton,
K. C. 1995, “Substitution cystoplasty for intractable interstitial cystitis”, Br
J Urol., vol. 76, no. 2, pp. 172-174.
Hukkanen, V., Haarala, M., Nurmi, M., Klemi, P., & Kiilholma, P. 1996,
“Viruses and interstitial cystitis: adenovirus genomes cannot be demonstrated in urinary bladder biopsies”, Urol.Res., vol. 24, no. 4, pp. 235-238.
Hunner, G. L. A rare type of bladder ulcer. Further notes, with a report of
eighteen cases. JAMA 70[4], 203-212. 1-26-1918.
Ref Type: Journal (Full)
Hunner, G. L. 1915, “A rare type of bladder ulcer in women; report of cases”,
Boston Med Surg Journal, vol. 172, pp. 660-664.
Hurst, R. E., Parsons, C. L., Roy, J. B., & Young, J. L. 1993, “Urinary glycosaminoglycan excretion as a laboratory marker in the diagnosis of interstitial cystitis”, J Urol., vol. 149, no. 1, pp. 31-35.
Hurst, R. E., Roy, J. B., Min, K. W., Veltri, R. W., Marley, G., Patton, K.,
Shackelford, D. L., Stein, P., & Parsons, C. L. 1996, “A deficit of chondroitin
sulfate proteoglycans on the bladder uroepithelium in interstitial cystitis”,
Urology, vol. 48, no. 5, pp. 817-821.
Hurst, R. E., Roy, J. B., & Parsons, C. L. 1997, “The role of glycosaminoglycans
in normal bladder physiology and the pathophysiology of interstitial cystitis,” in Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia,
pp. 93-100.
Hurst, R. 2003, “A deficit of proteoglycans on the bladder uroepithelium in
interstitial cystitis”, European Urology, vol. supplement 2, pp. 10-13.
Interstitial Cystitis Association. Novel therapy for IC is found not to be effective. Cafe ICA volume 4 number 2 . 3-11-2004.
Ref Type: Internet Communication
Irwin, P. & Galloway, N. T. 1993, “Impaired bladder perfusion in interstitial
cystitis: a study of blood supply using laser Doppler flowmetry”, J Urol., vol.
149, no. 4, pp. 890-892.
Irwin, P. & Galloway, N. T. M. 1992, “Re: Pelvic pain without pelvic organs
(Letter)”, Journal of Urology, vol. 148, pp. 1265-1266.
Irwin, P. P. & Galloway, N. T. 1994, “Surgical management of interstitial cystitis”, Urol.Clin.North Am., vol. 21, no. 1, pp. 145-151.
Irwin, P. P., Hammonds, W. D., & Galloway, N. T. 1993, “Lumbar epidural
blockade for management of pain in interstitial cystitis”, Br J Urol., vol. 71,
no. 4, pp. 413-416.
Ito, T., Miki, M., & Yamada, T. 2000, “Interstitial cystitis in Japan”, BJU.Int.,
vol. 86, no. 6, pp. 634-637.
Ito, T., Stein, P. C., Parsons, C. L., & Schmidt, J. D. 1998, “Elevated stress protein in transitional cells exposed to urine from interstitial cystitis patients”,
Int.J Urol., vol. 5, no. 5, pp. 444-448.
Ito, T., Tomoe, H., Ueda, T., Yoshimura, N., Sant, G., & Hanno, P. 2003,
“Clinical symptoms scale for interstitial cystitis for diagnosis and for following the course of the disease”, Int.J Urol., vol. 10 Suppl, p. S24-S26.
Jacob, J., Ludgate, C. M., Forde, J., & et.al. 1978, “Recent observations on the
ultrastructure of human urothelilum”, Cell Tiss Res, vol. 193, pp. 543-560.
Jacobo, E., Stamler, F. W., & Culp, D. A. 1974, “Interstitial cystitis followed by
total cystectomy”, Urology, vol. 3, no. 4, pp. 481-485.
Janicki, T. 2003, “Chronic pelvic pain as a form of complex regional pain syndrome”, Clin.Obstet.Gynecol., vol. 46, no. 4, pp. 797-803.
AL
Hanno, P. M., Buehler, J., & Wein, A. J. 1989, “Use of amitriptyline in the treatment of interstitial cystitis”, J Urol., vol. 141, no. 4, pp. 846-848.
Hanno, P. M., Fritz, R., & Wein, A. J. 1978, “Heparin as an antibacterial agent
in rabbit bladder”, Urology, vol. 12, pp. 411-415.
Hanno, P. M., Landis, J. R., Matthews-Cook, Y., Kusek, J., & et.al. 1999a,
“Interstitial cystitis: issues of definition”, Urol Integr Invest, vol. 4, no. 4, pp.
291-295.
Hanno, P. M., Landis, J. R., Matthews-Cook, Y., Kusek, J., & Nyberg, L., Jr.
1999b, “The diagnosis of interstitial cystitis revisited: lessons learned from
the National Institutes of Health Interstitial Cystitis Database study”, J
Urol., vol. 161, no. 2, pp. 553-557.
Hanno, P. M. & Tomaszewski, J. E. 1982, “Bladder carcinoma after urinary
diversion”, JAMA, vol. 248, p. 2885.
Hanno, P. M. & Wein, A. J. 1991, “Conservative therapy of interstitial cystitis”,
Semin.Urol., vol. 9, no. 2, pp. 143-147.
Hanno, P. M. & Wein, A. J. 1987, “Medical treatment of interstitial cystitis
(other than Rimso-50/Elmiron)”, Urology, vol. 29, no. 4 Suppl, pp. 22-26.
Hanus, T., Zamecnik, L., Jansky, M., Jarolim, L., Povysil, C., & Benett, R. 2001,
“The comparison of clinical and histopathologic features of interstitial cystitis”, Urology, vol. 57, no. 6 Suppl 1, p. 131.
Haq, A., Morsy, M., & Webb, R. J. 2004, “A study to detect Helicobacter pylori
in fresh and archival specimens from patients with interstitial cystitis, using
amplification methods”, BJU.Int., vol. 93, no. 3, p. 423.
Harn, S. D., Keutel, H. J., & Weaver, R. G. 1973, “Immunologic and histologic
evaluation of the urinary bladder wall after group A streptococcal infection”, Investigative Urology, vol. 11, pp. 55-64.
Harrington, D. S., Fall, M., & Johansson, S. L. 1990, “Interstitial cystitis: bladder mucosa lymphocyte immunophenotyping and peripheral blood flow
cytometry analysis”, J Urol., vol. 144, no. 4, pp. 868-871.
Harrison, S. C. W., Ferguson, D. R., & Hanley, M. R. 1990, “Effect of capsaicin
on the rabbit urinary bladder.
What is the function of sensory nerves that contain substance P?”, British
Journal of Urology, vol. 66, pp. 155-161.
Hedelin, H. H., Mardh, P. A., Brorson, J. E., Fall, M., Moller, B. R., &
Pettersson, K. G. 1983, “Mycoplasma hominis and interstitial cystitis”, Sex
Transm.Dis., vol. 10, no. 4 Suppl, pp. 327-330.
Held, P. J., Hanno, P. M., & Wein, A. J. 1990, “Epidemiology of interstitial cystitis: 2,” in Interstitial Cystitis, P. M. Hanno et al., eds., Springer-Verlag,
London, pp. 29-48.
Hellstrom, H. R., Davis, B. K., & Shonnard, J. W. 1979, “Eosinophilic cystitis.
A study of 16 cases”, Am.J Clin.Pathol., vol. 72, no. 5, pp. 777-784.
Herbst, R. H., Baumrucker, G. O., & German, K. L. 1937, “Elusive ulcer
(Hunner) of the bladder with an experimental study of the etiology”, Am J
Surg, vol. 38, pp. 152-167.
Heritz, D. M., Lacroix, J. M., Batra, S. D., Jarvi, K. A., Beheshti, B., &
Mittelman, M. W. 1997, “Detection of eubacteria
ubacteria in interstitial cystitis by
16S rDNA amplification”, J Urol., vol. 158, no. 6, pp. 2291-2295.
Hofmeister, M. A., He, F., Ratliff, T. L., Mahoney, T., & Becich, M. J. 1997,
“Mast cells and nerve fibers in interstitial
interstitial cystitis (IC): an algorithm for histologic diagnosis via quantitative image analysis and morphometry
(QIAM)”, Urology, vol. 49, no. 5A Suppl, pp. 41-47.
Hohenfellner, M., Nunes, L., Schmidt, R. A., Lampel, A., Thuroff, J. W., &
itis: increased sympathetic innervation
Tanagho, E. A. 1992, “Interstitial cystitis:
and related neuropeptide synthesis”, J Urol., vol. 147, no. 3, pp. 587-591.
Hohlbrugger, G. 1999, “Urinary potassium and the overactive bladder”, BJU
International, vol. 83, no. suppl 2, pp. 22-28.
Hohlbrugger, G. 1997, “Disintegrity of the vesical blood-urine barrier in
interstitial cystitis: a vicious circle,” in Interstitial Cystitis, G. R. Sant, ed.,
Lippincott-Raven, Philadelphia, pp. 87-92.
Hohlbrugger, G., Frauscher, F., Strasser, H., Stenzl, A., & Bartsch, G. 1998,
“Topical heparin therapy normalizes urothelial permeability and vesical
blood flow in urgency/frequency syndrome, urge incontinence and
reversible interstitial cystitis”, European Urology, vol. 33, no. S1, p. A38.
Hohlbrugger, G. & Riedl, C. 2000, “Non-bacterial cystitis”, Curr.Opin.Urol.,
vol. 10, no. 5, pp. 371-380.
Holm-Bentzen, M. 1989, “Pathology and pathophysiology of painful bladder
diseases”, Urol.Int., vol. 44, no. 6, pp. 327-331.
Holm-Bentzen, M., Jacobsen, F., Nerstrom, B., Lose, G., Kristensen, J. K.,
Pedersen, R. H., Krarup, T., Feggetter, J., Bates, P., Barnard, R., & . 1987a, “A
prospective double-blind clinically controlled multicenter trial of sodium
pentosanpolysulfate in the treatment of interstitial cystitis and related
painful bladder disease”, J Urol., vol. 138, no. 3, pp. 503-507.
Holm-Bentzen, M., Jacobsen, F., Nerstrom, B., Lose, G., Kristensen, J. K.,
Pedersen, R. H., Krarup, T., Feggetter, J., Bates, P., Barnard, R., & . 1987b,
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
SECTION III
48
AL
Keay, S. K., Szekely, Z., Conrads, T. P., Veenstra, T. D., Barchi, J. J., Jr., Zhang,
C. O., Koch, K. R., & Michejda, C. J. 2004b, “An antiproliferative factor from
interstitial cystitis patients is a frizzled 8 protein-related sialoglycopeptide”,
Proc.Natl.Acad.Sci.U.S.A, vol. 101, no. 32, pp. 11803-11808.
Keay, S. K., Zhang, C. O., Shoenfelt, J., Erickson, D. R., Whitmore, K., Warren,
J. W., Marvel, R., & Chai, T. 2001, “Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor-like growth factor,
and epidermal growth factor as urine markers for interstitial cystitis”,
Urology, vol. 57, no. 6 Suppl 1, pp. 9-14.
Keller, M. L., McCarthy, D. O., & Neider, R. S. 1994, “Measurement of symptoms of interstitial cystitis. A pilot study”, Urol.Clin.North Am., vol. 21, no.
1, pp. 67-71.
Kelly, J. D., Young, M. R., Johnston, S. R., & Keane, P. F. 1998, “Clinical
response to an oral prostaglandin analogue in patients with interstitial cystitis”, Eur.Urol., vol. 34, no. 1, pp. 53-56.
Kennelly, M. J. & Konnak, J. W. “Intravesical cromolyn sodium for treatment
of interstitial cystitis -- a double-blind placebo controlled pilot study”,
NIDDK, Bethesda, MD, p. 64.
Kerr, W. S., Jr. 1971, “Interstitial cystitis: treatment by transurethral resection”,
J Urol., vol. 105, no. 5, pp. 664-666.
Keselman, I., Austin, P., Anderson, J., & et.al. 1995, “Cystectomy and urethrectomy for disabling interstitial cystitis: A long term followup”, Journal of
Urology, vol. 153, p. 290A.
Khanna, O. P. & Loose, J. H. 1990, “Interstitial cystitis treated with intravesical doxorubicin”, Urology, vol. 36, no. 2, pp. 139-142.
Khoury, J. M., Timmons, S. L., Corbel, L., & et.al. 1992, “Complications of
enterocystoplasty”, Urology, vol. 40, pp. 9-13.
Kim, Y. S., Levin, R. M., Wein, A. J., & Longhurst, P. A. 1992, “Effects of sensitization on the permeability of urothelium in guinea pig urinary bladder”,
J Urol., vol. 147, no. 1, pp. 270-273.
Kirkemo, A., Peabody, M., Diokno, A. C., Afanasyev, A., Nyberg, L. M., Jr.,
Landis, J. R., Cook, Y. L., & Simon, L. J. 1997, “Associations among urodynamic findings and symptoms in women enrolled in the Interstitial Cystitis
Data Base (ICDB) Study”, Urology, vol. 49, no. 5A Suppl, pp. 76-80.
Kirkemo, A. K., Miles, B. J., & Peters, J. M. 1990, “Use of amitriptyline in the
treatment of interstitial cystitis”, Journal of Urology, vol. 143, p. 279A.
Kisman, O. K., Nijeholt, A. A., & van Krieken, J. H. 1991, “Mast cell infiltration in intestine used for bladder aug
augmentation in interstitial cystitis”,
J.Urol., vol. 146, no. 4, pp. 1113-1114.
Klutke, C. G., Bullock, A. D., & Ratliff, T. L. 1997, “Experimental autoimmune
cystitis (EAC): an autoimmune model for interstitial cystitis,” in Interstitial
Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia, pp. 33-46.
Koff, S. A. & Byard, M. A. 1988, “The daytime urinary frequency syndrome of
childhood”, Journal of Urology, vol. 140, pp. 1280-1281.
Kohli, N., Sze, E. H. M., & Karram, M. M. 1997, “Gynecologic aspects of interstitial cystitis,” in Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven,
Philadelphia, pp. 153-164.
Kohn, I. J., Filer-Maerten, S., Whitmore, K. E., Hanno, P. M., & Ruggieri, M.
R. 1998, “Lack of effect following repeated in vivo exposure of the rabbit
urinary bladder to urine from interstitial cystitis patients at low infusion
volumes”, Neurourol.Urodyn., vol. 17, no. 2, pp. 147-152.
Kontras, S. B., Bodenbender, J. G., McClave, C. R., & Smith, J. P. 1971,
“Interstitial cystitis in chronic granulomatous disease”, J.Urol., vol. 105, no.
4, pp. 575-578.
Korting, G. E., Smith, S. D., Wheeler, M. a., Weiss, R. M., & Foster, H. E., Jr.
1999, “A randomized double-blind trial of oral L-arginine for treatment of
interstitial cystitis”, J Urol., vol. 161, no. 2, pp. 558-565.
Koziol, J. A. 1994, “Epidemiology of interstitial cystitis”, Urol.Clin.North Am.,
vol. 21, no. 1, pp. 7-20.
Koziol, J. A., Clark, D. C., Gittes, R. F., & Tan, E. M. 1993, “The natural history of interstitial cystitis: a survey of 374 patients”, J Urol., vol. 149, no. 3, pp.
465-469.
Kruger, J. M., Osborne, C. A., Goyal, S. M., & et.al. 1991, “Clinical evaluation
of cats with lower urinary tract disease”, J Am Vet Med Assoc, vol. 199, pp.
211-216.
Kuo, H. C. 2003, “Urodynamic study and potassium sensitivity test for women
with frequency-urgency syndrome and interstitial cystitis”, Urol.Int., vol.
71, no. 1, pp. 61-65.
Kuo, H. C. 2001, “Urodynamic results of intravesical heparin therapy for
women with frequency urgency syndrome and interstitial cystitis”, J
Formos.Med Assoc, vol. 100, no. 5, pp. 309-314.
Lagunoff, F. D., Martin, T. W., & Read, G. 1983, “Agents that release histamine
from mast cells”, Ann Rev Pharmacol Toxicol, vol. 23, pp. 331-351.
Lamm, D. L. & Gittes, R. F. 1977, “Inflammatory carcinoma of the bladder and
interstitial cystitis”, J.Urol., vol. 117, no. 1, pp. 49-51.
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
Jasmin, L., Janni, G., J, M. H., & Rabkin, S. D. 1998, “Activation of CNS circuits produing a neurogenic cystitis: evidence for centrally induced peripheral inflammation”, Journal of Neuroscience, vol. 18, pp. 10016-10029.
Jepsen, J. V., Sall, M., Rhodes, P. R., Schmidt, D., Messing, E., & Bruskewitz, R.
C. 1998, “Long-term experience with pentosanpolysulfate in interstitial
cystitis”, Urology, vol. 51, no. 3, pp. 381-387.
Johansson, S. L. & Fall, M. 1994, “Pathology of interstitial cystitis”,
Urol.Clin.North Am., vol. 21, no. 1, pp. 55-62.
Johansson, S. L. & Fall, M. 1990, “Clinical features and spectrum of light
microscopic changes in interstitial cystitis”, J Urol., vol. 143, pp. 1118-1124.
Johansson, S. L., Ogawa, K., & Fall, M. 1997, “The pathology of interstitial cystitis,” in Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia,
pp. 143-152.
Jokinen, E. J., Alfthan, O. S., & Oravisto, K. J. 1972, “Antitissue antibodies in
interstitial cystitis”, Clin.Exp.Immunol., vol. 11, no. 3, pp. 333-339.
Jokinen, E. J., Lassus, A., Salo, O. P., & Alfthan, O. 1972, “Discoid lupus erythematosus and interstitial cystitis. The presence of bound immunoglobulins in the bladder mucosa”, Ann.Clin.Res., vol. 4, no. 1, pp. 23-25.
Jokinen, E. J., Oravisto, K. J., & Alfthan, O. S. 1973, “The effect of cystectomy
on antitissue antibodies in interstitial cystitis”, Clin.Exp.Immunol., vol. 15,
no. 3, pp. 457-460.
Jones, C. A. & Nyberg, L. 1997, “Epidemiology of interstitial cystitis”, Urology,
vol. 49, no. 5A Suppl, pp. 2-9.
Kang, J., Wein, A. J., & Levin, R. M. 1992, “Bladder functional recovery following acute overdistention”, Neurourol Urodyn, vol. 11, pp. 253-260.
Kaplan, A. P., Haak-Frendscho, M., Fuci, A., & et.al. 1985, “A histamine-releasing factor from activated human mononuclear cells”, J Immunol, vol. 135,
pp. 2027-2032.
Kaplan, S. A., Ikeguchi, E. F., Santarosa, R. P., D'Alisera, P. M., Hendricks, J.,
Te, A. E., & Miller, M. I. 1996, “Etiology of voiding dysfunction in men less
than 50 years of age”, Urology, vol. 47, pp. 836-839.
Kastrup, J., Hald, T., Larsen, S., & Nielsen, V. G. 1983, “Histamine content and
mast cell count of detrusor muscle in patients with interstitial cystitis and
other types of chronic cystitis”, Br J Urol., vol. 55, no. 5, pp. 495-500.
Katske, F., Shoskes, D. A., Sender, M., Poliakin, R., Gagliano, K., & Rajfer, J.
2001, “Treatment of interstitial cystitis with a quercetin supplement”,
Tech.Urol., vol. 7, no. 1, pp. 44-46.
Kau, A. L., Hunstad, D. A., & Hultgren, S. J. 2005, “Interaction of uropathogenic Escherichia coli with host uroepithelium”, Current Opinion in
Microbiology, vol. 8, no. 1, pp. 54-59.
Keay, S., Kleinberg, M., Zhang, C. O., Hise, M. K., & Warren, J. W. 2000,
“Bladder epithelial cells from patients with interstitial cystitis produce an
inhibitor of heparin-binding epidermal growth factor-like growth factor
production”, J.Urol., vol. 164, no. 6, pp. 2112-2118.
Keay, S., Seillier-Moiseiwitsch, F., Zhang, C. O., Chai, T. C., & Zhang, J. 2003a,
“Changes in human bladder epithelial cell gene expression associated with
interstitial cystitis or antiproliferative factor treatment”, Physiol Genomics,
vol. 14, no. 2, pp. 107-115.
Keay, S. & Warren, J. W. 1998, “A hypothesis for the etiology of interstitial cystitis based upon inhibition of bladder epithelial repair”, Med.Hypotheses,
vol. 51, no. 1, pp. 79-83.
Keay, S., Warren, J. W., Zhang, C. O., Tu, L. M., Gordon, D. A., & Whitmore,
K. E. 1999, “Antiproliferative activity is present in bladder but not renal
pelvic urine from interstitial cystitis patients”, J Urol., vol. 162, no. 4, pp.
1487-1489.
Keay, S., Zhang, C. O., Baldwin, B. R., Jacobs, S. C., & Warren, J. W. 1998a,
“Polymerase chain reaction amplification of bacterial 16S rRNA genes in
interstitial cystitis and control patient bladder biopsies”, J Urol., vol. 159,
no. 1, pp. 280-283.
Keay, S., Zhang, C. O., Chai, T., Warren, J., Koch, K., Grkovic, D., Colville, H.,
& Alexander, R. 2004a, “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, vol. 63,
no. 1, pp. 22-26.
Keay, S., Zhang, C. O., Hise, M. K., Hebel, J. R., Jacobs, S. C., Gordon, D.,
Whitmore, K., Bodison, S., Gordon, N., & Warren, J. W. 1998b, “A diagnostic in vitro urine assay for interstitial cystitis”, Urology, vol. 52, no. 6, pp.
974-978.
Keay, S., Zhang, C. O., Shoenfelt, J. L., & Chai, T. C. 2003b, “Decreased in vitro
proliferation of bladder epithelial cells from patients with interstitial cystitis”, Urology, vol. 61, no. 6, pp. 1278-1284.
Keay, S., Zhang, C. O., Trifillis, A. L., Hise, M. K., Hebel, J. R., Jacobs, S. C., &
Warren, J. W. 1996, “Decreased 3H-thymidine incorporation by human
bladder epithelial cells following exposure to urine from interstitial cystitis
patients”, J Urol., vol. 156, no. 6, pp. 2073-2078.
49
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
Logadottir, Y. R., Ehren, I., Fall, M., Wiklund, N. P., Peeker, R., & Hanno, P. M.
2004, “Intravesical nitric oxide production discriminates between classic
and nonulcer interstitial cystitis”, J.Urol, vol. 171, no. 3, pp. 1148-1150.
Lose, G., Frandsen, B., Hojensgard, J. C., Jespersen, J., & Astrup, T. 1983,
“Chronic interstitial cystitis: increased levels of eosinophil cationic protein
in serum and urine and an ameliorating effect of subcutaneous heparin”,
Scand.J Urol.Nephrol., vol. 17, no. 2, pp. 159-161.
Lose, G., Frandsen, B., Holm-Bentzen, M., Larsen, S., & Jacobsen, F. 1987,
“Urine eosinophil cationic protein in painful bladder disease”, Br.J.Urol.,
vol. 60, no. 1, pp. 39-42.
Lose, G., Jespersen, J., Frandsen, B., Hojensgard, J. C., & Astrup, T. 1985,
“Subcutaneous heparin in the treatment of interstitial cystitis”, Scand.J
Urol.Nephrol., vol. 19, no. 1, pp. 27-29.
Lotenfoe, R. R., Christie, J., Parsons, A., Burkett, P., Helal, M., & Lockhart, J.
L. 1995, “Absence of neuropathic pelvic pain and favorable psychological
profile in the surgical selection of patients with disabling interstitial cystitis”, J Urol., vol. 154, no. 6, pp. 2039-2042.
Lotz, M., Villiger, P., Hugli, T., Koziol, J., & Zuraw, B. L. 1994, “Interleukin-6
and interstitial cystitis”, J Urol., vol. 152, no. 3, pp. 869-873.
Low, P. A. & Dotson, R. M. 1998, “Symptomatic treatment of painful neuropathy”, JAMA, vol. 280, pp. 1863-1864.
Lowe, E. M., Anand, P., Terenghi, G., Williams-Chestnut, R. E., Sinicropi, D.
V., & Osborne, J. L. 1997, “Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial
cystitis”, Br J Urol., vol. 79, no. 4, pp. 572-577.
Lubeck, D. P., Whitmore, K., Sant, G. R., Alvarez-Horine, S., & Lai, C. 2001,
“Psychometric validation of the O'leary-Sant interstitial cystitis symptom
index in a clinical trial of pentosan polysulfate sodium”, Urology, vol. 57,
no. 6 Suppl 1, pp. 62-66.
Luber-Narod, J., Austin-Ritchie, T., Hollins III, C., Menon, M., Malhotra, R.
K., Baker, S., & Carraway, R. E. 1997, “Role of substance P in several models of bladder inflammation”, Urol Res, vol. 25, pp. 395-399.
Lukban, J., Whitmore, K., Kellogg-Spadt, S., Bologna, R., Lesher, A., &
Fletcher, E. 2001, “The effect of manual physical therapy in patients diagnosed with interstitial cystitis, high-t
high-tone pelvic floor dysfunction, and
sacroiliac dysfunction”, Urology, vol. 57, no. 6 Suppl 1, pp. 121-122.
Lundberg, J. O., Ehren, I., Jansson, O., Adolfsson, J., Lundberg, J. M.,
Weitzberg, E., Alving, K., & Wiklund, N. P. 1996, “Elevated nitric oxide in
the urinary bladder in infectious and noninfectious cystitis”, Urology, vol.
48, no. 5, pp. 700-702.
Lundeberg, T., Liedberg, H., Nordling, L., Theodorsson, E., Owzarski, A., &
Ekman, P. 1993, “Interstitial cystitis: correlation with nerve fibres, mast cells
and histamine”, Br.J.Urol., vol. 71, no. 4, pp. 427-429.
Lungi, F., Nicita, G., Selli, C., & et.al. 1984, “Clinical aspects of augmentation
enterocystoplasties”, Eur Urol, vol. 10, pp. 159-163.
Luo, Y. 2005, “A potential modality for interstitial cystitis: intravesical use of
anti-inflammatory peptide RDP58”, J Urol, vol. 173, p. 340.
Lutgendorf, S. K. & Kreder, K. J. 2005, “Central and peripheral mechanisms in
interstitial symptoms”, J Urol, vol. 173, p. 682.
Lutgendorf, S. K., Kreder, K. J., Rothrock, N. E., Hoffman, A., Kirschbaum, C.,
Sternberg, E. M., Zimmerman, M. B., & Ratliff, T. L. 2002, “Diurnal cortisol variations and symptoms in patients with interstitial cystitis”, J Urol.,
vol. 167, no. 3, pp. 1338-1343.
Lutgendorf, S. K., Kreder, K. J., Rothrock, N. E., Ratliff, T. L., & Zimmerman,
B. 2000, “Stress and symptomatology in patients with interstitial cystitis: a
laboratory stress model”, J Urol., vol. 164, no. 4, pp. 1265-1269.
Lutgendorf, S. K., Latini, J. M., Rothrock, N., Zimmerman, M. B., & Kreder, K.
J., Jr. 2004, “Autonomic response to stress in interstitial cystitis”, J.Urol, vol.
172, no. 1, pp. 227-231.
Lynes, W. L., Flynn, S. D., Shortliffe, L. D., Lemmers, M., Zipser, R., Roberts,
L. J., & Stamey, T. A. 1987, “Mast cell involvement in interstitial cystitis”, J
Urol., vol. 138, no. 4, pp. 746-752.
Lynes, W. L., Flynn, S. D., Shortliffe, L. D., & Stamey, T. A. 1990, “The histology of interstitial cystitis”, Am.J Surg.Pathol., vol. 14, no. 10, pp. 969-976.
Lynes, W. L., Shortliffe, L. D., & Stamey, T. A. 1990, “Urinary myotropic substances in interstitial cystitis”, Journal of Urology, vol. 143, p. 373A.
Lynn, R. B. & Friedman, L. S. 1993, “Irritable bowel syndrome”, New England
Journal of Medicine, vol. 329, pp. 1940-1945.
MacDermott, J. P., Charpied, G. C., Tesluk, H., & Stone, A. R. 1991a, “Can histological assessment predict the outcome in interstitial cystitis?”, Br J Urol.,
vol. 67, no. 1, pp. 44-47.
MacDermott, J. P., Charpied, G. L., Tesluk, H., & Stone, A. R. 1990, “Recurrent
interstitial cystitis following cystoplasty: fact or fiction?”, J.Urol., vol. 144,
no. 1, pp. 37-40.
AL
Lane, D. A. & Adams, L. 1993, “Non-anticoagulant uses of heparin”, N Engl J
Med, vol. 329, pp. 129-130.
LaRock, D. R. & Sant, G. R. 1995, “Intravesical clorpactin for refractory interstitial cystitis”, Infections in Urology, vol. Sept/Oct, pp. 151-157.
Larsen, S., Thompson, S. A., Hald, T., Barnard, R. J., Gilpin, C. J., Dixon, J. S.,
& Gosling, J. A. 1982, “Mast cells in interstitial cystitis”, Br J Urol., vol. 54,
no. 3, pp. 283-286.
Lasanen, L. T., Tammela, T. L., Kallioinen, M., & Waris, T. 1992, “Effect of
acute distension on cholinergic innervation of the rat urinary bladder”,
Urol.Res., vol. 20, no. 1, pp. 59-62.
Latham, R. H. & Stamm, W. E. 1984, “Urethral syndrome in women”, Urol
Clin North Am, vol. 11, pp. 95-101.
Lavelle, J. P., Apodaca, G., Meyers, S. A., Ruiz, W. G., & Zeidel, M. L. 1998,
“Disruption of guinea pig urinary bladder permeabliity barrier in noninfectious cystitis”, Am J Physiol, vol. 274, p. F205-F214.
Lavelle, J. P., Meyers, S. A., Ruiz, W. G., Buffington, C. A., Zeidel, M. L., &
Apodaca, G. 2000, “Urothelial pathophysiological changes in feline interstitial cystitis: a human model”, Am.J.Physiol Renal Physiol, vol. 278, no. 4, p.
F540-F553.
Lavelle, J. P., Yoshiyama, M., Doty, D. A., Meyers, S. A., & et.al. 1999,
“Capsaicin antagonizes elevated urothelial permeability in rat bladder
induced by pelvic nerve stimulation”, Journal of Urology, vol. 161S, p. 25.
Lazzeri, M., Beneforti, P., Benaim, G., Maggi, C. A., Lecci, A., & Turini, D.
1996, “Intravesical capsaicin for treatment of severe bladder pain: a randomized placebo controlled study”, Journal of Urology, vol. 156, pp. 947952.
Lazzeri, M., Beneforti, P., Turini, D., Barbagli, G., & Palminteri, E. 2000,
“Single dose of intravesical resiniferatoxin for the treatment of interstitial
cystitis -- preliminary results of a randomised controlled study”, Journal of
Urology, vol. 163S, p. 60.
Lepinard, V., Saint-Andre, J. P., & Rognon, L. M. 1984, “[Interstitial cystitis.
Current aspects]”, J.Urol.(Paris), vol. 90, no. 7, pp. 455-465.
Leppilahti, M., Tammela, T. L., Huhtala, H., & Auvinen, A. 2002, “Prevalence
of symptoms related to interstitial cystitis in women: a population based
study in Finland”, J Urol., vol. 168, no. 1, pp. 139-143.
Leppilahti, M., Tammela, T. L., Huhtala, H., Kiilholma, P., Leppilahti, K., &
Auvinen, A. 2003, “Interstitial cystitis-like urinary symptoms among
patients with Sjogren's syndrome: a population-based study in Finland”,
Am.J Med, vol. 115, no. 1, pp. 62-65.
Letourneau, R., Pang, X., Sant, G. R., & Theoharides, T. C. 1996,
“Intragranular activation of bladder mast cells and their association with
nerve processes in interstitial cystitis”, Br J Urol., vol. 77, no. 1, pp. 41-54.
Levander, H. 2003, “[Sensory sensitization, part II: Pathophysiology in dysfunctional disorders. Understanding the inner life of the nerve pathways
may explain hitherto unexplainable symptoms]”, Lakartidningen, vol. 100,
no. 18, pp. 1618-4.
Levin, R. M., Lavkar, R. M., Monson, F. C., Witowski, B. A., Wein, A. J., Hanno,
P. M., & Ruggieri, M. R. 1988, “Effect of chronic nitrofurantoin on the rabbit urinary bladder”, J Urol., vol. 139, no. 2, pp. 400-404.
Lewi, H. J. 1996, “Cimetidine in the treatme
treatment
nt of interstitial cystitis”, British
Journal of Urology, vol. 77, no. suppliment 1, p. 28.
Liebert, M. 1997, “Bladder cell acitvation and mucosal immunity in interstistitis, G. R. Sant, ed., Lippincott-Raven,
tial cystitis,” in Interstitial Cystitis,
Philadelphia, pp. 117-122.
Liebert, M., Wedemeyer, G., Stein, J. A., Washington, R., Jr., Faerber, G., Flint,
A., & Grossman, H. B. 1993, “Evidence for urothelial cell activation in interstitial cystitis”, J Urol., vol. 149, no. 3, pp. 470-475.
Lilius, H. G., Oravisto, K. J., & Valtonen, E. J. 1973, “Origin of pain in interstitial cystitis. Effect of ultrasound treatment on the concomitant levator ani
spasm syndrome”, Scand.J Urol.Nephrol., vol. 7, no. 2, pp. 150-152.
Lilly, J. D. & Parsons, C. L. 1990, “Bladder surface glycosaminoglycans is a
human epithelial permeability barrier”, Surg Gynecol Obstet, vol. 171, pp.
493-496.
Linn, J. F., Hohenfellner, M., Roth, S., Dahms, S. E., Stein, R., Hertle, L.,
Thuroff, J. W., & Hohenfellner, R. 1998, “Treatment of interstitial cystitis:
comparison of subtrigonal and supratrigonal cystectomy combined with
orthotopic bladder substitution”, J Urol., vol. 159, no. 3, pp. 774-778.
Littleton, R. H., Farah, R. N., & Cerny, J. C. 1982, “Eosinophilic cystitis: an
uncommon form of cystitis”, J Urol., vol. 127, no. 1, pp. 132-133.
Liu, Y. K., Harty, J. I., Steinbock, G. S., & et.al. 1990, “Treatment of radiation
or cyclophosphamide induced hemorrhagic cystitis using conjugated estrogen”, Journal of Urology, vol. 144, pp. 41-43.
Lloyd, L. K. 1999, “Surgical treatment of interstitial cystitis”, AUA News, vol.
September/October, p. 12.
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
SECTION III
50
AL
2000, “Quality of life among women with interstitial cystitis”, J Urol., vol.
164, no. 2, pp. 423-427.
Miller, C. H., MacDermott, J. P., Quattrocchi, K. B., Broderick, G. A., & Stone,
A. R. 1992, “Lymphocyte function in patients with interstitial cystitis”, J
Urol., vol. 147, no. 3, pp. 592-595.
Miller, J. L., Bavendam, T. G., & Berger, R. E. 1997, “Interstitial cystitis in men,”
in Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia, pp.
165-168.
Miller, J. L., Rothman, I., Bavendam, T. G., & Berger, R. E. 1995,
“Prostatodynia and interstitial cystitis: one and the same?”, Urology, vol. 45,
no. 4, pp. 587-590.
Minogiannis, P., El Mansoury, M., Betances, J. A., Sant, G. R., & Theoharides,
T. C. 1998, “Hydroxyzine inhibits neurogenic bladder mast cell activation”,
Int.J Immunopharmacol., vol. 20, no. 10, pp. 553-563.
Moen, M. & Stokstad, T. 2002, “A long term followup study of women with
asymptomatic endometriosis diagnosed incidentally at sterilization”,
Fertility Sterility, vol. 78, pp. 773-776.
Moldwin, R. & Kushner, L. The diagnostic value of interstitial cystitis questionnaires. J Urol. 171[4 suppliment], 96. 5-9-2004.
Ref Type: Abstract
Moller, N. E. 1978, “Carbenicillin-induced hemorrhagic cystitis”, Lancet, vol.
2, p. 946.
Monga, M., Percival, C., & Zupkas, P. 2001, “Intravesical ethanol as quantitative measure of bladder hyperpermeability”, J Endourol., vol. 15, no. 6, pp.
641-644.
Moore, K. H., Nickson, P., Richmond, D. H., Sutherst, J. R., Manasse, P. R., &
Helliwell, T. R. 1992, “Detrusor mast cells in refractory idiopathic instability”, Br J Urol., vol. 70, no. 1, pp. 17-21.
Morales, A., Emerson, L., Nickel, J. C., & Lundie, M. 1996, “Intravesical
hyaluronic acid in the treatment of refrac
refractory interstitial cystitis”, J Urol.,
vol. 156, no. 1, pp. 45-48.
Moran, P. A., Dwyer, P. L., Carey, M. P., Maher, C. F., & Radford, N. J. 1999,
“Oral methotrexate in the management of refractory interstitial cystitis”,
Aust.N.Z.J Obstet.Gynaecol., vol. 39, no. 4, pp. 468-471.
Moskowitz, M. O., Byrne, D. S., Callahan, H. J., Parsons, C. L., Valderrama, E.,
& Moldwin, R. M. 1994, “Decreased expression of a glycoprotein component of bladder surface mucin (GP1) in interstitial cystitis”, J Urol., vol. 151,
no. 2, pp. 343-345.
Mulholland, S. G. & Byrne, D. S. 1994, “Interstitial cystitis”, J Urol., vol. 152,
no. 3, pp. 879-880.
Mulholland, S. G., Hanno, P., Parsons, C. L., Sant, G. R., & Staskin, D. R. 1990,
“Pentosan polysulfate sodium for therapy of interstitial cystitis. A doubleblind placebo-controlled clinical study”, Urology, vol. 35, no. 6, pp. 552558.
Murnaghan, G. F., Saalfeld, J., & Farnsworth, R. H. 1970, “Interstitial cystitis-treatment with Chlorpactin WCS 90”, Br J Urol., vol. 42, no. 6, p. 744.
Murphy, D. M., Zincke, H., & Utz, D. C. 1982, “Interstitial cystitis”, J Urol., vol.
128, no. 3, p. 606.
Myers, D. L. & Aguilar, V. C. 2002, “Gynecologic manifestations of interstitial
cystitis”, Clin.Obstet.Gynecol., vol. 45, no. 1, pp. 233-241.
Naber, S. P. 1994, “Molecular pathology--diagnosis of infectious disease”, N
Engl J Med, vol. 331, pp. 1212-1215.
Neal, D. E., Jr., Dilworth, J. P., & Kaack, M. B. 1991, “Tamm-Horsfall autoantibodies in interstitial cystitis”, J Urol., vol. 145, no. 1, pp. 37-39.
Nesse, R. M. 1999, “Proximate and evolutionary studies of anxiety, stress and
depression: synergy at the interface”, Neurosci Biobehav Rev, vol. 23, pp.
895-903.
Nguan, C., Franciosi, L. G., Butterfield, N. N., Macleod, B. A., Jens, M., &
Fenster, H. N. 2005, “A prospective, double-blind, randomized cross-over
study evaluating changes in urinary pH for relieving the symptoms of
interstitial cystitis”, BJU International, vol. 95, no. 1, pp. 91-94.
Nickel, J. C., Barkin, J., Forrest, J., Mosbaugh, P. G., Hernandez-Graulau, J.,
Kaufman, D., Lloyd, K., Evans, R. J., Parsons, C. L., & Atkinson, L. E. 2005,
“Randomized, double-blind, dose-ranging study of pentosan polysulfate
sodium for interstitial cystitis”, Urology, vol. 65, no. 4, pp. 654-658.
Nickel, J. C., Downey, J., Morales, A., Emerson, L., & Clark, J. 1998, “Relative
efficacy of various exogenous glycosaminoglycans in providing a bladder
surface permeablility barrier”, Journal of Urology, vol. 160, pp. 612-614.
Nickel, J. C., Emerson, L., & Cornish, J. 1993, “The bladder mucus (glycosaminoglycan) layer in interstitial cystitis”, J.Urol., vol. 149, no. 4, pp.
716-718.
Nielsen, K. K., Kromann-Andersen, B., Steven, K., & Hald, T. 1990, “Failure of
combined supratrigonal cystectomy and Mainz ileocecocystoplasty in
intractable interstitial cystitis: is histology and mast cell count a reliable
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
MacDermott, J. P., Miller, C. H., Levy, N., & Stone, A. R. 1991b, “Cellular
immunity in interstitial cystitis”, J Urol., vol. 145, no. 2, pp. 274-278.
Makela, M. & Heliovaara, M. 1991, “Prevalence of primary fibromyalgia in the
Finnish population”, Br.Med Journal, vol. 303, pp. 216-219.
Marinoff, S. C. & Turner, M. L. C. 1991, “Vulvar vestibulitis syndrome: An
overview”, J Obstet Gynecol, vol. 165, pp. 1228-1234.
Markwell, S. J. 2001, “Physical therapy managment of pelvi/perineal and perianal syndromes”, World J Urol, vol. 19, pp. 194-199.
Martins, S. M., Darlin, D. J., Lad, P. M., & Zimmern, P. E. 1994, “Interleukin1B: a clinically relevant urinary marker”, J Urol., vol. 151, no. 5, pp. 11981201.
Marx, C. M. & Alpert, S. E. 1984, “Ticarcillin-induced cystitis”, A J Dis Child,
vol. 138, pp. 670-672.
Mattila, J. 1982, “Vascular immunopathology in interstitial cystitis”,
Clin.Immunol.Immunopathol., vol. 23, no. 3, pp. 648-655.
Mattila, J., Harmoinen, A., & Hallstrom, O. 1983, “Serum immunoglobulin
and complement alterations in interstitial cystitis”, Eur.Urol., vol. 9, no. 6,
pp. 350-352.
Mattila, J. & Linder, E. 1984, “Immunoglobulin deposits in bladder epithelium and vessels in interstitial cystitis: possible relationship to circulating
anti-intermediate
filament
autoantibodies”,
Clin.Immunol.Immunopathol., vol. 32, no. 1, pp. 81-89.
Mayer, R. & Interstial cystitis clinical trials group. A randomized, multicenter
clinical trial to evaluate the efficacy of intravesical bacillus calmette guerin
(BCG), for the treatment of interstitial cystitis. J Urol . 2005.
Ref Type: In Press
McCahy, P. J. & Styles, R. A. 1995, “Prolonged bladder distension: experience
in the treatment of detrusor overactivity and interstitial cystitis”, Eur.Urol.,
vol. 28, no. 4, pp. 325-327.
McCormack, W. M. 1990, “Two urogenital sinus syndromes. Interstitial cystitis and focal vulvitis”, J Reprod.Med, vol. 35, no. 9, pp. 873-876.
McCormick, N. B. 1997, “Psychological aspects of interstitial cystitis,” in
Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia, pp. 193204.
Mcdougald M, L. C. The diagnosis of interstitial
ial cystitis: Is histology helpful ?
Int.Urogynecol.J.Pelvic.Floor.Dysfunct. 14[Suppl 1], S40-S41. 2003.
Ref Type: Abstract
McGuire, E. J., Lytton, B., & Cornog, J. L., Jr. 1973, “Interstitial cystitis following colocystoplasty”, Urology, vol. 2, no. 1, pp. 28-29.
McGuire, E. J., Shi-chun, Z., Horwinski, E. R., & et.al. 1983, “Treatment of
motor and sensory detrusor instability by electrical stimulation”, Journal of
Urology, vol. 129, pp. 78-79.
McInerney, P. D., Vanner, T. F., Matenhelia, S., & Stephenson, T. P. 1991,
“Assessment of the long-term results of subtrigonal phenolisation”, Br J
Urol., vol. 67, no. 6, pp. 586-587.
McQuay H 2003, “Numbers need to care”, Pain., vol. 106, no. 3, pp. 213-214.
McQuay HJ & Moore RA 1997, “Antidepressants and chronic pain”, BMJ., vol.
314, no. 7083, pp. 763-764.
Meadows, E. 1999, “Treatments for patients with pelvic pain”, Urologic
Nursing, vol. 19, pp. 33-35.
Meirowsky, A. M. 1969, “The management of chronic interstitial cystitis by
differential sacral neurotomy”, J Neurosurg., vol. 30, no. 5, pp. 604-607.
Melchior, D., Packer, C. S., Johnson, T. C., & Kaefer, M. 2003, “Dimethyl sulfoxide: does it change the functional properties of the bladder wall?”,
J.Urol., vol. 170, no. 1, pp. 253-258.
Mendelowitz, F. & Moldwin, R. 1997, “Complementary approaches in the
management of interstitial cystitis,” in Interstitial Cystitis, G. R. Sant, ed.,
Lippincott-Raven, Philadelphia, pp. 235-240.
Messing, E., Pauk, D., Schaeffer, A., Nieweglowski, M., Nyberg, L. M., Jr.,
Landis, J. R., Cook, Y. L., & Simon, L. J. 1997, “Associations among cystoscopic findings and symptoms and physical examination findings in
women enrolled in the Interstitial Cystitis Data Base (ICDB) Study”,
Urology, vol. 49, no. 5A Suppl, pp. 81-85.
Messing, E. M. 1994, “Interstitial cystitis”, J Urol., vol. 151, no. 2, pp. 355-356.
Messing, E. M. & Freiha, F. S. 1979, “Complication of Clorpactin WCS90 therapy for interstitial cystitis”, Urology, vol. 13, no. 4, pp. 389-392.
Messing, E. M. & Stamey, T. A. 1978, “Interstitial cystitis: early diagnosis,
pathology, and treatment”, Urology, vol. 12, no. 4, pp. 381-392.
Meulders, Q., Michel, C., Marteau, P., Grange, J. D., Mougenot, B., Ronco, P.,
& Mignon, F. 1992, “Association of chronic interstitial cystitis, protein-losing enteropathy and paralytic ileus with seronegative systemic lupus erythematosus: case report and review of the literature”, Clin.Nephrol., vol. 37,
no. 5, pp. 239-244.
Michael, Y. L., Kawachi, I., Stampfer, M. J., Colditz, G. A., & Curhan, G. C.
51
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
Pang, X., Marchand, J., Sant, G. R., Kream, R. M., & Theoharides, T. C. 1995b,
“Increased number of substance P positive nerve fibres in interstitial cystitis”, Br J Urol., vol. 75, no. 6, pp. 744-750.
Pang, X., Sant, G., & Theoharides, T. C. 1998, “Altered expression of bladder
mast cell growth factor receptor (c-kit) in interstitial cystitis”, Urology, vol.
51, no. 6, pp. 939-944.
Parekh, M. H., Chichester, P., Lobel, R. W., Aikawa, K., & Levin, R. M. 2004,
“Effects of castration on female rabbit bladder physiology and morphology”, Urology, vol. 64, no. 5, pp. 1048-1051.
Parker, C., Steele, S., Raghavan, R., Evans, G., Cranney, A., Robb, S., & Nickel,
J. C. 2004, “Hypersensitivity reaction associated with intravesical bacillus
Calmette-Guerin for interstitial cystitis”, J Urol, vol. 172, no. 2, p. 537.
Parrish, J. 1836, “Tic doloureux of the urinary bladder,” in Practical observations on strangulated hernia and some of the diseases of the urinary
organs, Key and Biddle, Philadelphia, pp. 309-313.
Parsonnet, J., Friedman, G. D., P, V. D., & et.al. 1991, “Helicobacter pylori
infection and the risk of gastric carcinoma”, N Engl J Med, vol. 325, pp.
1127-1136.
Parsons, C. L. 1994, “A model for the function of glycosaminoglycans in the
urinary tract”, World J Urol, vol. 12, pp. 38-42.
Parsons, C. L. Interstitial cystitis: new concepts in pathogenesis, diagnosis, and
management. AUA News 5[4], 20-31. 2000.
Ref Type: Magazine Article
Parsons, C. L. 1986, “Successful management of radiation cystitis with sodium pentosanpolysulfate”, Journal of Urology, vol. 136, pp. 813-814.
Parsons, C. L. 1990, “Interstitial cystitis: Clinical manifestations and diagnostic criteria in over 200 cases”, Neurourol Urodyn, vol. 9, pp. 241-250.
Parsons, C. L. 1993, “The role of the glycosaminoglycan layer in bladder
defense mechanisms and interstitial cystitis”, Int Urogynecol J, vol. 4, pp.
373-379.
Parsons, C. L. & Albo, M. 2002, “Intravesical potassium sensitivity in patients
with prostatitis”, J Urol., vol. 168, no. 3, pp. 1054-1057.
Parsons, C. L., Bautista, S. L., Stein, P. C., & Zupkas, P. 2000, “Cyto-injury factors in urine: a possible mechanism for the development of interstitial cystitis”, J Urol., vol. 164, no. 4, pp. 1381-1384.
Parsons, C. L., Benson, G., Childs, S. J., Hanno, P., Sant, G. R., & Webster, G.
1993, “A quantitatively controlled method to study prospectively interstitial
cystitis and demonstrate the efficacy of pentosanpolysulfate”, J Urol., vol.
150, no. 3, pp. 845-848.
Parsons, C. L., Bullen, M., Kahn, B. S., Stanford, E. J., & Willems, J. J. 2001,
“Gynecologic presentation of interstitial cystitis as detected by intravesical
potassium sensitivity”, Obstet.Gynecol., vol. 98, no. 1, pp. 127-132.
Parsons, C. L., Dell, J., Stanford, E. J., Bullen, M., Kahn, B. S., Waxell, T., &
Koziol, J. A. 2002a, “Increased prevalence of interstitial cystitis: previously
unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity”, Urology, vol. 60,
no. 4, pp. 573-578.
Parsons, C. L., Dell, J., Stanford, E. J., Bullen, M., Kahn, B. S., & Willems, J. J.
2002b, “The prevalence of interstitial cystitis in gynecologic patients with
pelvic pain, as detected by intravesical potassium sensitivity”, Am.J
Obstet.Gynecol., vol. 187, no. 5, pp. 1395-1400.
Parsons, C. L., Greenberger, M., Gabal, L., Bidair, M., & Barme, G. 1998, “The
role of urinary potassium in the pathogenesis and diagnosis of interstitial
cystitis”, J Urol., vol. 159, no. 6, pp. 1862-1866.
Parsons, C. L., Housley, T., Schmidt, J. D., & Lebow, D. 1994a, “Treatment of
interstitial cystitis with intravesical heparin”, Br J Urol., vol. 73, no. 5, pp.
504-507.
Parsons, C. L. & Hurst, R. E. 1990, “Decreased urinary uronic acid levels in
individuals with interstitial cystitis”, J Urol., vol. 143, no. 4, pp. 690-693.
Parsons, C. L. & Koprowski, P. F. 1991, “Interstitial cystitis: successful management by increasing urinary voiding intervals”, Urology, vol. 37, no. 3, pp.
207-212.
Parsons, C. L., Lilly, J. D., & Stein, P. 1991, “Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis)”, J Urol., vol. 145, no. 4, pp. 732-735.
Parsons, C. L., Schmidt, J. D., & Pollen, J. J. 1983, “Successful treatment of
interstitial cystitis with sodium pentosanpolysulfate”, J Urol., vol. 130, no.
1, pp. 51-53.
Parsons, C. L. & Stein, P. 1990, “Role of toxic urine in interstitial cystitis”,
Journal of Urology, vol. 143, p. 373A.
Parsons, C. L., Stein, P. C., Bidair, M., & et.al. 1994b, “Abnormal sensitivity to
intravesical potassium in interstitial cystitis and radiation cystitis”,
Neurourol Urodyn, vol. 13, pp. 515-520.
Parsons, C. L., Stein, P. C., Bidair, M., & Lebow, D. 1994c, “Abnormal sensitivity to intravesical potassium in interstitial cystitis and radiation cystitis”,
Neurourol.Urodyn., vol. 13, no. 5, pp. 515-520.
AL
predictor for the outcome of surgery?”, J.Urol., vol. 144, no. 2 Pt 1, pp. 255258.
Nigro, D. A. & Wein, A. J. 1997, “Interstitial cystitis: clinical and endoscopic
features,” in Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven,
Philadelphia, pp. 137-142.
Nigro, D. A., Wein, A. J., Foy, M., Parsons, C. L., Williams, M., Nyberg, L. M.,
Jr., Landis, J. R., Cook, Y. L., & Simon, L. J. 1997, “Associations among cystoscopic and urodynamic findings for women enrolled in the Interstitial
Cystitis Data Base (ICDB) Study”, Urology, vol. 49, no. 5A Suppl, pp. 86-92.
NIH Consensus Development Panel 1994, “Helicobacter pylori in peptic ulcer
disease”, JAMA, vol. 272, pp. 65-69.
Nordling, J. 2004, “Interstitial cystitis: how should we diagnose it and treat it
in 2004?”, Curr.Opin.Urol, vol. 14, no. 6, pp. 323-327.
Nordling, J., Anderson, J. B., Mortensen, S., Bouchelouche, K., Horn, T., Hald,
T., & and the Copenhagen IC study group. Clinical outcome in patients
with interstitial cystitis, relative to detrusor myopathy. Poster 42 Research
Insights into Interstitial cystitis, NIDDK Washington Oct 30-Nov 1, 2003 .
11-1-2003.
Ref Type: Abstract
Nordling, J., Anjum, F. H., Bade, J. J., Bouchelouche, K., Bouchelouche, P.,
Cervigni, M., Elneil, S., Fall, M., Hald, T., Hanus, T., Hedlund, H.,
Hohlbrugger, G., Horn, T., Larsen, S., Leppilahti, M., Mortensen, S.,
Nagendra, M., Oliveira, P. D., Osborne, J., Riedl, C., Sairanen, J., Tinzl, M.,
& Wyndaele, J. J. 2004, “Primary evaluation of patients suspected of having
interstitial cystitis (IC)”, Eur.Urol., vol. 45, no. 5, pp. 662-669.
Novicki, D. E., Larson, T. R., & Swanson, S. K. 1998, “Interstitial cystitis in
men”, Urology, vol. 52, no. 4, pp. 621-624.
Nurse, D. E., Parry, J. R., & Mundy, A. R. 1991, “Problems in the surgical treatment of interstitial cystitis”, Br.J.Urol., vol. 68, no. 2, pp. 153-154.
O'Connor, V. J. 1955, “Clorpactin WCS-90 in the treatment of interstitial cystitis”, Q.Bull.Northwest.Univ Med Sch, vol. 29, no. 4, pp. 392-395.
O'leary, M. P. & Sant, G. 1997, “The interstitial cystitis symptom and problem
indices: rationale, development, and application,” in Interstitial Cystitis, G.
Sant, ed., Lippincott-Raven, Philadelphia, pp. 271-276.
O'leary, M. P., Sant, G. R., Fowler, F. J., Jr., Whitmore, K. E., & Spolarich-Kroll,
J. 1997, “The interstitial cystitis symptom index and problem index”,
Urology, vol. 49, no. 5A Suppl, pp. 58-63.
O'Reilly, B. A., Dwyer, P. L., Hawthorne, G., Cleaver, S., Thomas, E., Rosamilia,
A., & Fynes, M. 2004, “Transdermal posterior tibial nerve laser therapy is
not effective in women with interstitial cystitis”, J.Urol, vol. 172, no. 5 Pt 1,
pp. 1880-1883.
Ochs, R. L., Stein, T. W., Jr., Peebles, C. L., Gittes, R. F., & Tan, E. M. 1994,
“Autoantibodies in interstitial cystitis”,
itis”, J Urol., vol. 151, no. 3, pp. 587-592.
Ochs, R. L. & Tan, E. M. 1997, “Autoimmunity and interstitial cystitis,” in
Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia, pp. 4752.
Okragly, A. J., Niles, A. L., Saban, R., Schmidt, D., Hoffman, R. L., Warner, T.
F., Moon, T. D., Uehling, D. T., & Haak-Frendscho, M. 1999, “Elevated
tryptase, nerve growth factor, neurotrophin-3 and glial cell line-derived
neurotrophic factor levels in the urine of interstitial cystitis and bladder
cancer patients”, J Urol., vol. 161, no. 2, pp. 438-441.
Onwude, J. L. & Selo-Ojeme, D. O. 2003, “Pregnancy outcomes following the
diagnosis of interstitial cystitis”, Gynecol.Obstet.Invest, vol. 56, no. 3, pp.
160-162.
Oravisto, K. J. 1975, “Epidemiology of interstitial cystitis”, Ann.Chir
Gynaecol.Fenn., vol. 64, no. 2, pp. 75-77.
Oravisto, K. J. 1980, “Interstitial cystitis as an autoimmune disease. A review”,
Eur.Urol., vol. 6, no. 1, pp. 10-13.
Oravisto, K. J. & Alfthan, O. S. 1976, “Treatment of interstitial cystitis with
immunosuppression and chloroquine derivatives”, Eur.Urol., vol. 2, no. 2,
pp. 82-84.
Oyama, I. A., Rejba, A., Lukban, J. C., Fletcher, E., Kellogg-Spadt, S., Holzberg,
A. S., & Whitmore, K. E. 2004, “Modified Thiele massage as therapeutic
intervention for female patients with interstitial cystitis and high-tone
pelvic floor dysfunction”, Urology, vol. 64, no. 5, pp. 862-865.
Palea, S., Artibani, W., Ostardo, E., Trist, D. G., & Pietra, C. 1993, “Evidence for
purinergic neurotransmission in human urinary bladder affected by interstitial cystitis”, J Urol., vol. 150, no. 6, pp. 2007-2012.
Pang, X., Boucher, W., Triadafilopoulos, G., Sant, G. R., & Theoharides, T. C.
1996, “Mast cell and substance P-positive nerve involvement in a patient
with both irritable bowel syndrome and interstitial cystitis”, Urology, vol.
47, no. 3, pp. 436-438.
Pang, X., Cotreau-Bibbo, M. M., Sant, G. R., & Theoharides, T. C. 1995a,
“Bladder mast cell expression of high affinity oestrogen receptors in
patients with interstitial cystitis”, Br J Urol., vol. 75, no. 2, pp. 154-161.
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
SECTION III
52
AL
Pool, T. L. 1967, “Interstitial cystitis: clinical considerations and treatment”,
Clin.Obstet.Gynecol., vol. 10, no. 1, pp. 185-191.
Pool, T. L. & Rives, H. F. 1944, “Interstitial cystitis: Treatment with silver
nitrate”, Journal of Urology, vol. 51, pp. 520-525.
Porru, D., Campus, G., Tudino, D., Valdes, E., Vespa, A., Scarpa, R. M., & Usai,
E. 1997, “Results of treatment of refractory interstitial cystitis with intravesical hyaluronic acid”, Urol.Int., vol. 59, no. 1, pp. 26-29.
Porru, D., Politano, R., Gerardini, M., Giliberto, G. L., Stancati, S., Pasini, L.,
Tinelli, C., & Rovereto, B. 2004, “Different clinical presentation of interstitial cystitis syndrome”, Int.Urogynecol.J.Pelvic.Floor.Dysfunct., vol. 15, no.
3, pp. 198-202.
Porru, D., Tinelli, C., Gerardini, M., Giliberto, G. L., Stancati, S., & Rovereto,
B. 2005, “Evaluation of urinary and general symptoms and correlation with
other clinical parameters in interstitial cystitis patients”, Neurourol
Urodyn, vol. 24, pp. 69-73.
Portenoy, R. K., Dole, V., Joseph, H., Lowinson, J., & et.al. 1997, “Pain management and chemical dependency”, JAMA, vol. 278, pp. 592-593.
Portenoy, R. K. & Foley, K. M. 1986, “Chronic use of opioid analgesics in nonmalignant pain: Report of 38 cases”, Pain pp. 171-186.
Potts, J. M., Ward, A. M., & Rackley, R. R. 2000, “Association of chronic urinary symptoms in women and Ureaplasma urealyticum”, Urology, vol. 55,
no. 4, pp. 486-489.
Powell, N. B. & Powell, E. B. 1949, “The female urethra: A clinico-pathological study”, Journal of Urology, vol. 61, pp. 557-570.
Pranikoff, K. & Constantino, G. 1998, “The use of amitriptyline in patients
with urinary frequency and pain”, Urology, vol. 51, no. 5A Suppl, pp. 179181.
Prendergast, S. & Weiss, J. M. 2003, “Screening for musculoskeletal causes of
pelvic pain”, Clin.Obstet.Gynecol., vol. 46, no. 4, pp. 773-782.
Press, S. M., Moldwin, R., Kushner, L., & et.al. 1995, “Decreased expression of
GP-51 glycosaminoglycan in cats afflicted with feline interstitial cystitis”,
Journal of Urology, vol. 153, p. 288 A.
Price, D. T., Maloney, K. E., Ibrahim, G. K., Cundiff, G. W., & et.al. 1996,
“Vesical endometriosis: report of two cases and review of the literature”,
Urology, vol. 48, pp. 639-643.
Propert, K. J., Payne, C., Kusek, J. W., & Nyberg, L. M. 2002, “Pitfalls in the
design of clinical trials for interstitial cystitis”, Urology, vol. 60, no. 5, pp.
742-748.
Propert, K. J., Schaeffer, A. J., Brensinger, C. M., Kusek, J. W., Nyberg, L. M., &
Landis, J. R. 2000, “A prospective study of interstitial cystitis: results of longitudinal followup of the interstitial cystitis data base cohort. The
Interstitial Cystitis Data Base Study Group”, J Urol., vol. 163, no. 5, pp.
1434-1439.
Rackley, R., Frenkl, T., & Abdelmalak, J. 2005, “Botulinum toxin: the promise
of therapy for complex voiding dysfunctions”, Contemp Urol no. February,
pp. 38-52.
Rajkumar, G. N. & Conn, I. G. 2004, “Botulinum toxin: a new dimension in
the treatment of lower urinary tract dysfunction”, Urology, pp. 2-8.
Rashid, H. H., Reeder, J. E., O'Connell, M. J., Zhang, C. O., Messing, E. M., &
Keay, S. K. 2004, “Interstitial cystitis antiproliferative factor (APF) as a cellcycle modulator”, BMC.Urol, vol. 4, no. 1, p. 3.
Ratliff, T. L., Klutke, C. G., & McDougall, E. M. 1994, “The etiology of interstitial cystitis”, Urol.Clin.North Am., vol. 21, no. 1, pp. 21-30.
Ratner, V. & Slade, D. 1997, “Interstitial cystitis: a women's health perspective,”
in Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia, pp.
257-260.
Ratner, V., Slade, D., & Whitmore, K. E. 1992, “Interstitial cystitis: A bladder
disease finds legitimacy”, Journal of Women's Health, vol. 1, pp. 63-68.
Ray, W., Meredith, S., Thapa, P., Hall, K., & Murray, K. 2004, “Cyclic antidepressants and the risk of sudden cardiac death”, Clin Pharmacol Ther, vol.
75, pp. 234-241.
Rees, J., Wade, T., Levy, D., Colford, J., & Hilton, J. 2005, “Changes in beliefs
identify unblinding in randomized controlled trials: a method to meet
CONSORT guidelines”, Contemporary Clinical Trials, vol. 26, pp. 25-37.
Reinhart, H., Obedeanu, N., Hooton, T., & et.al. 1990, “Urinary excretion of
Tamm-Horsfall protein in women with recurrent urinary tract infections”,
Journal of Urology, vol. 144, pp. 1185-1187.
Renshaw, D. C. 1988, “Desipramine for interstitial cystitis”, JAMA, vol. 260,
no. 3, p. 341.
Rice, L., Kennedy, D., & Veach, A. 1998, “Pentosan induced cerebral sagittal
sinus thrombosis: a variant of heparin induced thrombocytopenia”, Journal
of Urology, vol. 160, p. 2148.
Rickard, A. & Lagunoff, D. “A novel model for the role of mast cells in interstitial cystitis”, National Institutes of Health, Bethesda, Maryland, p. 69.
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
Parsons, C. L. & Tatsis, V. 2004, “Prevalence of interstitial cystitis in young
women”, Urology, vol. 64, no. 5, pp. 866-870.
Parsons, C. L., Zupkas, P., & Parsons, J. K. 2001, “Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome”, Urology,
vol. 57, no. 3, pp. 428-432.
Parsons, C. L. 2005, “Successful downregulation of bladder sensory nerves
with combination of heparin and alkalinized lidocaine in patients with
interstitial cystitis”, Urology, vol. 65, no. 1, pp. 45-48.
Parsons, C. L., Rosenberg, M. T., Sassani, P., Ebrahimi, K., Koziol, J. A., &
Zupkas, P. 2005, “Quantifying symptoms in men with interstitial
cystitis/prostatitis, and its correlation with potassium-sensitivity testing”,
BJU International, vol. 95, no. 1, pp. 86-90.
Parsons, D. L., Boychuk, D., Hurst, R., & Callahan, H. 1990, “Bladder surface
glycosaminoglycans: An epithelial permeablility barrier”, Journal of
Urology, vol. 143, pp. 139-142.
Parsons, J. K. & Parsons, C. L. 2004, “The historical origins of interstitial cystitis”, J Urol., vol. 171, no. 1, pp. 20-22.
Patra, P. B., Tibbitts, F. D., & Westfall, D. P. “Endocrine status and urinary mast
cells: Possible relationship to interstitial cystitis”, National Institutes of
Health, Bethesda, Maryland, p. 70.
Peeker, R., Aldenborg, F., Dahlstrom, A., Johansson, S. L., Li, J. Y., & Fall, M.
2000a, “Increased tyrosine hydroxylase immunoreactivity in bladder tissue
from patients with classic and nonulcer interstitial cystitis”, J Urol., vol. 163,
no. 4, pp. 1112-1115.
Peeker, R., Aldenborg, F., & Fall, M. 1998, “The treatment of interstitial cystitis with supratrigonal cystectomy and ileocystoplasty: difference in outcome between classic and nonulcer disease”, J.Urol., vol. 159, no. 5, pp.
1479-1482.
Peeker, R., Enerback, L., Fall, M., & Aldenborg, F. 2000b, “Recruitment, distribution and phenotypes of mast cells in interstitial cystitis”, J Urol., vol. 163,
no. 3, pp. 1009-1015.
Peeker, R. & Fall, M. 2002, “Toward a precise definition of interstitial cystitis:
further evidence of differences in classic and nonulcer disease”, J Urol., vol.
167, no. 6, pp. 2470-2472.
Peeker, R., Haghsheno, M. A., Holmang, S., & Fall, M. 2000c, “Intravesical
bacillus Calmette-Guerin and dimethyl sulfoxide for treatment of classic
and nonulcer interstitial cystitis: a prospective, randomized double-blind
study”, J.Urol., vol. 164, no. 6, pp. 1912-1915.
Pelaez, E., Prieto Rodrigo, M. A., Munoz Zurdo, M. M., Sanchez Montero, F.
J., Santos, L. J., & Muriel, V. C. 2004, “[Epidural spinal cord stimulation for
interstitial cystitis]”, Rev Esp.Anestesiol.Reanim., vol. 51, no. 9, pp. 549-552.
Perez-Marrero, R., Emerson, L., & Juma, S. 1987, “Urodynamic studies in
interstitial cystitis”, Urology, vol. 29, no. 4 Suppl, pp. 27-30.
Perez-Marrero, R., Emerson, L. E., & Feltis, J. T. 1988, “A controlled study of
dimethyl sulfoxide in interstitial cystitis”, J Urol., vol. 140, no. 1, pp. 36-39.
Perez-Marrero, R., Emerson, L. E., Maharajh, D. O., & et.al. 1993,
“Prolongation of response to DMSO by heparin maintenance”, Urology,
vol. 41 (suppl), pp. 64-66.
Perzin, A. D., Hanno, P. M., & Ruggieri, M. R. 1991, “Effect of protamine and
IC urine on dye penetration across urothelium”, Journal of Urology, vol.
145, p. 259A.
Peters, K., Diokno, A., Steinert, B., Yuhico, M., Mitchell, B., Krohta, S., Gillette,
B., & Gonzalez, J. 1997, “The efficacy of intravesical Tice strain bacillus
Calmette-Guerin in the treatment of interstitial cystitis: a double-blind,
prospective, placebo controlled trial”, J Urol., vol. 157, no. 6, pp. 2090-2094.
Peters, K. M., Carey, J. M., & Konstandt, D. B. 2003, “Sacral neuromodulation
for the treatment of refractory interstitial cystitis: outcomes based on technique”, Int.Urogynecol.J Pelvic.Floor.Dysfunct., vol. 14, no. 4, pp. 223-228.
Peters, K. M., Diokno, A. C., & Steinert, B. W. 1999, “Preliminary study on urinary cytokine levels in interstitial cystitis: does intravesical bacille
Calmette-Guerin treat interstitial cystitis by altering the immune profile in
the bladder?”, Urology, vol. 54, no. 3, pp. 450-453.
Peters, K. M., Diokno, A. C., Steinert, B. W., & Gonzalez, J. A. 1998, “The efficacy of intravesical bacillus Calmette-Guerin in the treatment of interstitial
cystitis: long-term followup”, J Urol., vol. 159, no. 5, pp. 1483-1486.
Peters, K. M. & Konstandt, D. 2004, “Sacral neuromodulation decreases narcotic requirements in refractory interstitial cystitis”, BJU.Int., vol. 93, no. 6,
pp. 777-779.
Philip, J. & Irwin, P. 2004, “Can the potassium sensitivity test be explained by
an effect on detrusor activity? -- A prospective double-blinded study”, J
Urol, vol. 171, no. 4 (suppliment), p. 93.
Pontari, M. A., Hanno, P. M., & Ruggieri, M. R. 1999, “Comparison of bladder
blood flow in patients with and without interstitial cystitis”, J Urol., vol.
162, no. 2, pp. 330-334.
53
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
tis: animal models,” in Interstitial Cystitis, P. M. Hanno et al., eds., SpringerVerlag, London, pp. 49-62.
Ruggieri, M. R., Steinhardt, G. F., & Hanno, P. M. 1991, “Comparison of antiadherence activity of bladder extracts from interstitial cystitis patients with
recurrent urinary tract infections”, Semin.Urol., vol. 9, no. 2, pp. 136-142.
Rummans, T. A. 1994, “Nonopioid agents for treatment of acute and subacute
pain”, Mayo Clin Proc, vol. 69, pp. 481-490.
Ruoslahti, E. 1988, “Structure and biology of proteoglycans”, Ann Rev Cell
Biol, vol. 4, pp. 229-232.
Rupp, B. W., Perry, B. B., Griebling, T. L., Weigel, J. W., & et.al. 2000, “Quality
of life in women with interstitial cystitis following cystourethrectomy and
continent urinary diversion”, Journal of Urology, vol. 163S, p. 62.
Saban, R., Keith, I. M., & Bjorling, D. E. 1997, “Neuropeptide-mast cell interaction in interstitial cystitis,” in Interstitial Cystitis, G. R. Sant, ed.,
Lippincott-Raven, Philadelphia, pp. 53-66.
Saban, R., Saban, M. R., Nguyen, N. B., Hammond, T. G., & Wershil, B. K.
2001, “Mast cell regulation of inflammation and gene expression during
antigen-induced bladder inflammation in mice”, Physiol Genomics, vol. 7,
no. 1, pp. 35-43.
Sairanen, J., Forsell, T., & Ruutu, M. 2004, “Long-term outcome of patients
with interstitial cystitis treated with low dose cyclosporine A”, J.Urol, vol.
171, no. 6 Pt 1, pp. 2138-2141.
Sakakibara, R., Uchiyama, T., Yoshiyama, M., Yamanishi, T., & Hattori, T.
2003, “Urinary dysfunction in patients with systemic lupus erythematosis”,
Neurourol Urodyn, vol. 22, pp. 593-596.
Salavatore, S., Khullar, V., Cardozo, L., Anders, K., Zocchi, G., & Soligo, M.
2003, “Evaluating ambulatory urodynamics: a prospective study in asymptomatic women”, British Journal of Obstetrics and Gynaecology, vol. 110,
no. 1, pp. 83-84.
Sant, G. R. 1991, “Interstitial cystitis”, Monogr Urol, vol. 12, pp. 37-63.
Sant, G. R. 1987, “Intravesical 50% dimethyl sulfoxide (Rimso-50) in treatment of interstitial cystitis”, Urology, vol. 29, no. 4 Suppl, pp. 17-21.
Sant, G. R., Kilaru, P., & Ucci, A. A. 1988, “Mucosal mast cell contribution to
bladder mastocytosis in interstitial cystitis”, Journal of Urology, vol. 139, p.
276A.
Sant, G. R., Propert, K. J., Hanno, P. M., Burks, D., Culkin, D., Diokno, A. C.,
Hardy, C., Landis, J. R., Mayer, R., Madigan, R., Messing, E. M., Peters, K.,
Theoharides, T. C., Warren, J., Wein, A. J., Steers, W., Kusek, J. W., & Nyberg,
L. M. 2003, “A pilot clinical trial of oral pentosan polysulfate and oral
hydroxyzine in patients with interstitial cystitis”, J Urol., vol. 170, no. 3, pp.
810-815.
Sant, G. R. & Theoharides, T. C. 1994, “The role of the mast cell in interstitial
cystitis”, Urol.Clin.North Am., vol. 21, no. 1, pp. 41-53.
Sant, G. R., Theoharides, T. C., Letourneau, R., & Gelfand, J. 1997, “Interstitial
cystitis and bladder mastocytosis in a woman with chronic urticaria”,
Scand.J.Urol.Nephrol., vol. 31, no. 5, pp. 497-500.
Sasaki, K., Smith, C. P., Chuang, Y. C., Lee, J. Y., Kim, J. C., & Chancellor, M.
B. 2001, “Oral gabapentin (neurontin) treatment of refractory genitourinary tract pain”, Tech.Urol., vol. 7, no. 1, pp. 47-49.
Scheepens, W., Jongen, M., Nieman, F., deBie, R., Weil, E., & van Kerrebroeck,
P. 2002, “Predictive factors for sacral neuromodulation in chronic lower
urinary tract dysfunction”, Urology, vol. 60, no. 4, pp. 598-602.
Schmidt, R. A. 1993, “Neurostimulation of bladder and urethra,” in
Reconstructive Urology, G. Webster et al., eds., Blackwell Scientific
Publications, Boston, pp. 591-601.
Schmidt, R. A. 2001, “Urodynamic features of the pelvic pain patient and the
impact of neurostimulation on these parameters”, World J Urol, vol. 19, pp.
186-193.
Schmidt, R. A., Jonas, U., Oleson, K. A., Janknegt, R. A., Hassouna, M. M., &
et .al. 1999, “Sacral nerve stimulation for treatment of refractory urinary
urge incontinence”, Journal of Urology, vol. 162, pp. 352-357.
Schmidt, R. A. & Vapnek, J. M. 1991, “Pelvic floor behavior and interstitial cystitis”, Semin.Urol., vol. 9, no. 2, pp. 154-159.
Schulz, K. F., Chalmers, I., Hayes, R. J., & et.al. 1995, “Empirical evidence of
bias; dimensions of methodological quality associated with estimates of
treatment effects in controlled trials”, JAMA, vol. 273, pp. 408-412.
Sech, S. M., Montoya, J. D., Bernier, P. A., Barnboym, E., & et.al. 1998, “The
so-called “placebo effect” in benign prostatic hyperplasia treatment trials
represents partially a conditional regression to the mean induced by censoring”, Urology, vol. 51, pp. 242-250.
Seddon, J. M., Best, L., & Bruce, A. W. 1977, “Intestinocystoplasty in treatment
of interstitial cystitis”, Urology, vol. 10, no. 5, pp. 431-435.
Segura, J., Opitz, J., & Greene, L. 1979, “Prostatosis, prostatitis or pelvic floor
tesnion myalgia?”, J Urol, vol. 122, p. 168.
AL
Riedl, C. R., Knoll, M., Plas, E., Stephen, R. L., & Pfluger, H. 1997, “Intravesical
electromotive drug administration for the treatment of non-infectious
chronic cystitis”, Int.Urogynecol.J Pelvic.Floor.Dysfunct., vol. 8, no. 3, pp.
134-137.
Rivas, D. A., Chancellor, M. B., Shupp-Byrne, S., Shenot, P. J., McHugh, K., &
McCue, P. 1997, “Molecular marker for development of interstitial cystitis
in rat model: isoactin gene expression”, J.Urol., vol. 157, no. 5, pp. 19371940.
Roberto, P. J., Reich, J. D., Hirshberg, S., Knight, L., Hanno, P. M., & Ruggieri,
M. 1997, “Assessment of bladder permiability and sensation in interstitial
cystitis patients”, Journal of Urology, vol. 157, no. S, p. 317.
Roberts, R. O., Bergstralh, E. J., Bass, S. E., Lightner, D. J., Lieber, M. M., &
Jacobsen, S. J. 2003, “Incidence of physician-diagnosed interstitial cystitis in
Olmsted County: a community-based study”, BJU.Int., vol. 91, no. 3, pp.
181-185.
Robson, W. L. M. & Leung, A. K. C. 1993, “Extraordinary urinary frequency
syndrome”, Urology, vol. 42, pp. 321-324.
Rodriguez Villamil, L., Batista Miranda, J. E., Smet, C. E., & et.al. 1999,
“Supratrigonal cystectomy and enterocystoplasty as treatment of advanced
interstitial cystitis”, Urologia Integrada y de Investigacion, vol. 4, no. 4, p.
350=353.
Rofeim, O., Hom, D., Freid, R. M., & Moldwin, R. M. 2001, “Use of the
neodymium: YAG laser for interstitial cystitis: a prospective study”, J Urol.,
vol. 166, no. 1, pp. 134-136.
Rogers, R. 2003, “Pelvic denervation surgery: what the evidence and anatomy
teach us”, Clinical Obstetrics and Gynecology, vol. 46, no. 4, pp. 767-772.
Roppolo, J. R., Changfeng, T., Booth, C., Buffington, C. A., de Groat, W. C., &
Birder, L. A. 2005, “Bladder A afferent nerve activity in normal cats and cats
with feline interstitial cystitis”, J Urol, vol. 173, pp. 1011-1015.
Rosales, R. L., Ariumura, K., & Ikenaga, S. 1996, “Extrafusal and intrafusal
muscle effects in experimental botulinum toxin A injection”, Muscle Nerve,
vol. 19, pp. 488-496.
Rosamilia, A., Cann, L., Dwyer, P., Scurry, J., & Rogers, P. 1999a, “Bladder
microvasculature in women with interstitial cystitis”, J Urol., vol. 161, no. 6,
pp. 1865-1870.
Rosamilia, A., Clements, J. A., Dwyer, P. L., Kende, M., & Campbell, D. J.
1999b, “Activation of the kallikrein kinin system in interstitial cystitis”, J
Urol., vol. 162, no. 1, pp. 129-134.
Rosamilia, A., Dwyer, P. L., & Gibson, J. 1997, “Electromotive drug administration of lidocaine and dexamethasone followed by cystodistension in
women with interstitial cystitis”, Int.Urogynecol.J Pelvic.Floor.Dysfunct.,
vol. 8, no. 3, pp. 142-145.
Rosamilia, A., Igawa, Y., & Higashi, S. 2003, “Pathology of interstitial cystitis”,
Int.J Urol., vol. 10 Suppl, p. S11-S15.
Rose, N. R. & Bona, C. 1993, “Defining criteria for autoimmune diseases”,
Immunol Today, vol. 14, pp. 426-430.
Rothman, K. J. & Michels, K. B. 1994, “The continuing unethical use of placebo controls”, N Engl J Med pp. 394-398.
Rothrock, N. E., Lutgendorf, S. K., Hoffman, A., & Kreder, K. J. 2002,
“Depressive symptoms and quality of life in patients with interstitial cystitis”, J Urol., vol. 167, no. 4, pp. 1763-1767.
Rothrock, N. E., Lutgendorf, S. K., & Kreder, K. J. 2003, “Coping strategies in
patients with interstitial cystitis: relationships with quality of life and
depression”, J Urol., vol. 169, no. 1, pp. 233-236.
Rothrock, N. E., Lutgendorf, S. K., Kreder, K. J., Ratliff, T., & Zimmerman, B.
2001, “Stress and symptoms in patients with interstitial cystitis: a life stress
model”, Urology, vol. 57, no. 3, pp. 422-427.
Rovner, E., Propert, K. J., Brensinger, C., Wein, A. J., Foy, M., Kirkemo, A.,
Landis, J. R., Kusek, J. W., & Nyberg, L. M. 2000, “Treatments used in
women with interstitial cystitis: the interstitial cystitis data base (ICDB)
study experience. The Interstitial Cystitis Data Base Study Group”, Urology,
vol. 56, no. 6, pp. 940-945.
Rovner, E. S. & Wein, A. J. 1999, “Interstitial cystitis: clinical features”, Urologia
Integrada y de Investigacion, vol. 4, no. 4, pp. 307-314.
Rowbotham, M., Harden, N., Stacey, B., Bernstein, P., & et.al. 1998,
“Gabapentin for the treatment of postherpetic neuralgia”, JAMA, vol. 280,
pp. 1837-1842.
Ruggieri, M. R., Hanno, P. M., & Levin, R. M. 1987, “Nitrofurantoin not surface active agent in rabbit urinary bladder”, Urology, vol. 29, no. 5, pp. 534537.
Ruggieri, M. R., Hanno, P. M., Whitmore, K. E., & Balagani, R. K. 1993, “Effect
of repeated instillation of interstitial cystitis urine on the rabbit urinary
bladder”, Urology, vol. 42, no. 6, pp. 646-652.
Ruggieri, M. R., Monson, F. C., Levin, R. M., & et.al. 1990, “Interstitial cysti-
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
SECTION III
54
AL
G. R., & Theoharides, T. C. 1997, “Stress-induced bladder mast cell activation: implications for interstitial cystitis”, J Urol., vol. 157, no. 2, pp. 669672.
Spinelli, M., Bertapelle, P., Cappellano, F., Zanollo, A., Carone, R., Catanzaro,
F., Giardiello, G., & De Seta, F. 2001, “Chronic sacral neuromodulation in
patients with lower urinary tract symptoms: results from a national register”, J Urol, vol. 166, pp. 541-545.
Staehelin, L., Chalpowski, F., & Bonneville, M. 1972, “Luminal plasma membrane of the urinary bladder: 1. Three-dimensional reconstruction of
freeze-etch images”, J Cell Biol, vol. 53, p. 73.
Stamm, W. E. “Relationship of interstitial cystitis to the urethral syndrome”,
National Institutes of Health, Bethesda, Maryland, pp. 21-22.
Stamm, W. E., Wagner, K. F., Amsel, R., & et.al. 1980, “Causes of the acute urethral syndrome in women”, N Engl J Med, vol. 303, pp. 409-415.
Steers, W. D. & Tuttle, J. B. 1997, “Neurogenic inflammation and nerve growth
factor: possible roles in interstitial cystitis,” in Interstitial Cystitis, G. R.
Sant, ed., Lippincott-Raven, Philadelphia, pp. 67-76.
Stein, P. C., Santamaria, P. J., Kurtz, S. B., & Parsons, C. L. 1993, “Evaluation of
urothelial Tamm-Horsfall protein and serum antibody as a potential diagnostic marker for interstitial cystitis”, J Urol., vol. 150, no. 5 Pt 1, pp. 14051408.
Stein, P. C., Torri, A., & Parsons, C. L. 1999, “Elevated urinary norepinephrine
in interstitial cystitis”, Urology, vol. 53, no. 6, pp. 1140-1143.
Steinert, B. W., Diokno, A. C., Robinson, J. E., & Mitchell, B. A. 1994,
“Complement C3, eosinophil cationic pr
protein and symptom evaluation in
interstitial cystitis”, J Urol., vol. 151, no. 2, pp. 350-354.
Steinhoff, G., Ittah, B., & Rowan, S. 2002, “The efficacy of chondroitin sulfate
0.2% in treating interstitial cystitis”, Can.J Urol., vol. 9, no. 1, pp. 14541458.
Stewart, B. H., Branson, A. C., Hewitt, C. B., Kiser, W. S., & Straffon, R. A.
1971, “The treatment of patients with inter
interstitial cystitis, with special reference to intravesical DMSO”, Trans.Am.Assoc Genitourin.Surg., vol. 63, pp.
69-74.
Stewart, B. H., Branson, A. C., Hewitt, C. B., Kiser, W. S., & Straffon, R. A.
1972, “The treatment of patients with inter
interstitial cystitis, with special reference to intravesical DMSO”, J Urol., vol. 107, no. 3, pp. 377-380.
Stewart, B. H., Persky, L., & Kiser, W. S. 1968, “The use of dimethyl sulfoxide
(DMSO) in the treatment of interstitial cystitis”, Journal of Urology, vol. 98,
pp. 671-672.
Stewart, B. H. & Shirley, S. W. 1976, “Further experience with intravesical
dimethyl sulfoxide in the treatment of interstitial cystitis”, J.Urol., vol. 116,
no. 1, pp. 36-38.
Stone, A. R. 1991, “Treatment of voiding complaints and incontinence in
painful bladder syndrome”, Urol Clin North Am, vol. 18, pp. 317-325.
Stone, A. R., Vogelsang, P., Miller, C. H., & MacDermott, J. P. 1992, “TammHorsfall protein as a marker in interstitial cystitis”, J Urol., vol. 148, no. 5,
pp. 1406-1408.
Stone, N. N. 1994, “Nalmefene in the treatment of interstitial cystitis”,
Urol.Clin.North Am., vol. 21, no. 1, pp. 101-106.
Stones, R. 2003, “Pelvic vascular congestion -- half a century later”,
Clin.Obstet.Gynecol., vol. 46, no. 4, pp. 831-836.
Stout, L., Gerspach, J. M., Levy, S. M., Yun, S. K., Lad, P. M., Leach, G. E., &
Zimmern, P. E. 1995, “Dimethyl sulfoxide does not trigger urine histamine
release in interstitial cystitis”, Urology, vol. 46, no. 5, pp. 653-656.
Sun, Y. & Chai, T. C. 2004, “Up-regulation of P2X3 receptor during stretch of
bladder urothelial cells from patients with interstitial cystitis”, J.Urol, vol.
171, no. 1, pp. 448-452.
Sun, Y., Keay, S., De Deyne, P. G., & Chai, T. C. 2001, “Augmented stretch activated adenosine triphosphate release from bladder uroepithelial cells in
patients with interstitial cystitis”, J Urol., vol. 166, no. 5, pp. 1951-1956.
Sung, J. J. Y., Chung, S. C. S., Ling, T. K. W., & et.al. 1995, “Antibacterial treatment of gastric ulcers associated with Helicobacter pylori”, N Engl J Med,
vol. 332, pp. 139-142.
Sutton, C., Pooley, A., Ewen, S., & et.al 1997, “Followup report on a randomized controlled trial of laser laparoscopy in the treatment of pelvic pain
associated with minimal to moderate endometriosis”, Fertility Sterility, vol.
68, pp. 1070-1074.
Tan, E. M. 1989, “Antinuclear antibodies: diagnostic markers for autoimmune
diseases and probes for cell biology”, Adv Immunol, vol. 44, p. 93.
Taub, H. C. & Stein, M. 1994, “Bladder distention therapy for symptomatic
relief of frequency and urgency: a ten year review”, Urology, vol. 43, pp. 3639.
Teichman, J. M. & Nielsen-Omeis, B. J. 1999, “Potassium leak test predicts
outcome in interstitial cystitis”, J Urol., vol. 161, no. 6, pp. 1791-1794.
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
Serel, T. A., Soyupek, S., & Candir, O. 2004, “Association between mast cells
and bladder carcinoma”, Urol.Int., vol. 72, no. 4, pp. 299-302.
Seshadri, P., Emerson, L., & Morales, A. 1994, “Cimetidine in the treatment of
interstitial cystitis”, Urology, vol. 44, no. 4, pp. 614-616.
Shanberg, A. M. 1989, “Benign diseases of the bladder,” in Lasers in Urologic
Surgery, 2'nd edn, J. A. Smith, B. S. Stein, & R. C. Benson, eds., Year Book
Medical Publishers, Chicago, pp. 50-56.
Shanberg, A. M., Baghdassarian, R., & Tansey, L. A. 1985, “Treatment of interstitial cystitis with the neodymium-YAG laser”, J Urol., vol. 134, no. 5, pp.
885-888.
Shanberg, A. M. & Malloy, T. R. 1997, “Use of lasers in interstitial cystitis,” in
Interstitial Cystitis, G. R. Sant, ed., Lippincott-Raven, Philadelphia, pp. 215218.
Shea-O'Malley, C. C. & Sant, G. R. 1999, “Quality of life in interstitial cystitis”,
Urologia Integrada y de Investigacion, vol. 4, no. 4, pp. 303-306.
Shirley, S. W., Stewart, B. H., & Mirelman, S. 1978, “Dimethyl sulfoxide in
treatment of inflammatory genitourinary disorders”, Urology, vol. 11, no. 3,
pp. 215-220.
Sidh, S. M., Smith, S. P., Silber, S. B., & Young, J. D., Jr. 1980, “Eosinophilic cystitis: advanced disease requiring surgical intervention”, Urology, vol. 15, no.
1, pp. 23-26.
Siegel, A., Snyder, J., & Raz, S. 1990, “Surgical therapy of interstitial cystitis,”
in Interstitial Cystitis, P. M. Hanno et al., eds., Springer-Verlag, London, pp.
193-205.
Siegel, S., Paszkiewicz, E., Kirkpatrick, C., Hinkel, B., & Oleson, K. 2001,
“Sacral nerve stimulation in patients with chronic intractable pelvic pain”,
J Urol, vol. 166, pp. 1742-1745.
Silk, M. R. 1970, “Bladder antibodies in interstitial cystitis”, J Urol., vol. 103,
no. 3, pp. 307-309.
Simmons, J. L. 1961, “Interstitial cystitis: An explanation for the beneficial
effect of an antihistamine”, Journal of Urology, vol. 85, pp. 149-155.
Simmons, J. L. & Bunce, P. L. 1958, “On the use of an antihistamine in the
treatment of interstitial cystitis”, Am.Surg., vol. 24, no. 9, pp. 664-667.
Simon, L. J., Landis, J. R., Erickson, D. R., & Nyberg, L. M. 1997, “The
Interstitial Cystitis Data Base Study: concepts and preliminary baseline
descriptive statistics”, Urology, vol. 49, no. 5A Suppl, pp. 64-75.
Simons, F. 2004, “Advances in H1-antihistamines”, NEJM, vol. 351, no. 21, pp.
2203-2217.
Singh, G. & Thomas, D. G. 1996, “Interstitial cystitis: involvement of the intestine”, Eur.Urol., vol. 29, no. 3, pp. 322-324.
Sircus, S. I., Sant, G. R., & Ucci, A. A., Jr. 1988, “Bladder detrusor endometriosis mimicking interstitial cystitis”, Urology, vol. 32, no. 4, pp. 339-342.
Sirinian, E. & Payne, C. K. 2001, “Correlation of symptoms between 2 instruments among interstitial cystitis patients”, Urology, vol. 57, no. 6 Suppl 1,
pp. 124-125.
Siroky, M. B. 1994, “Is it interstitial cystitis?
itis? Diagnostic distinctions in reduced
bladder capacity.”, Contemp Urol, vol. July, pp. 13-22.
Skene, A. J. C. 1887, Diseases of the Bladder and Urethra in Women William
Wood, New York.
Slobodov, G., Feloney, M., Gran, C., Kyker, K. D., Hurst, R. E., & Culkin, D. J.
2004, “Abnormal expression of molecular markers for bladder impermeability and differentiation in the urothelium of patients with interstitial
cystitis”, J.Urol, vol. 171, no. 4, pp. 1554-1558.
Smith, B. H. & Dehner, L. P. 1972, “Chronic ulcerating interstitial cystitis
(Hunner's ulcer). A study of 28 cases”, Arch.Pathol., vol. 93, no. 1, pp. 7681.
Smith, C. P., Radziszewski, P., Borkowski, A., Somogyi, G. T., Boone, T. B., &
Chancellor, M. B. 2004, “Botulinum toxin a has antinociceptive effects in
treating interstitial cystitis”, Urology, vol. 64, no. 5, pp. 871-875.
Smith, G. L. & Christmas, T. J. 1996, “Interstitial ureteritis following cystectomy for interstitial cystitis”, Br J Urol., vol. 77, no. 4, pp. 607-608.
Smith, S. D., Wheeler, M. a., Foster, H. E., Jr., & Weiss, R. M. 1996, “Urinary
nitric oxide synthase activity and cyclic GMP levels are decreased with
interstitial cystitis and increased with urinary tract infections”, J Urol., vol.
155, no. 4, pp. 1432-1435.
Smith, S. D., Wheeler, M. a., Foster, H. E., Jr., & Weiss, R. M. 1997,
“Improvement in interstitial cystitis symptom scores during treatment
with oral L-arginine”, J Urol., vol. 158, no. 3 Pt 1, pp. 703-708.
Sorensen, R. 2003, “Chondroitin sulphate in the treatment of interstitial cystitis and chronic inflammatory disease of the urinary bladder”, Eur.Urol,
vol. suppliment 2, pp. 14-16.
Soucy, F. & Gregoire, M. 2005, “Efficacy of prednisone for severe refractory
ulcerative interstitial cystitis”, J Urol, vol. 173, pp. 841-843.
Spanos, C., Pang, X., Ligris, K., Letourneau, R., Alferes, L., Alexacos, N., Sant,
55
CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders
Physiology, Pathology, and Management of Upper Urinary Tract Diseases
van de Merwe, J. P., Yamada, T., & Sakamoto, Y. 2003, “Systemic aspects of
interstitial cystitis, immunology and linkage with autoimmune disorders”,
Int.J Urol., vol. 10 Suppl, p. S35-S38.
Van de, M. J., Kamerling, R., Arendsen, E., Mulder, D., & Hooijkaas, H. 1993,
“Sjogren's syndrome in patients with interstitial cystitis”, J Rheumatol., vol.
20, no. 6, pp. 962-966.
Van Kerrebroeck, P. E. V. 1999, “Electrical stimulation in the management of
interstitial cystitis”, Urologia Integrada y de Investigacion, vol. 4, no. 4, pp.
331-334.
van Ophoven, A. & Hertle, L. 2005, “Long term results of amitriptyline treatment for interstitial cystitis”, J Urol, vol. 173, no. 4, p. 86.
van, O. A., Oberpenning, F., & Hertle, L. 2002, “Long-term results of trigonepreserving orthotopic substitution enterocystoplasty for interstitial cystitis”, J Urol, vol. 167, no. 2 Pt 1, pp. 603-607.
van, O. A., Pokupic, S., Heinecke, A., & Hertle, L. 2004a, “A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the
treatment of interstitial cystitis”, J.Urol., vol. 172, no. 2, pp. 533-536.
van, O. A., Rossbach, G., Oberpenning, F., & Hertle, L. 2004b, “Hyperbaric
oxygen for the treatment of interstitial cystitis: long-term results of a
prospective pilot study”, Eur.Urol., vol. 46, no. 1, pp. 108-113.
Vander, A. J. 1995, Renal Physiology McGraw Hill Health Professions
Division, New York.
Vemulakonda, V., Somogyi, G., Kiss, S., Salas, N., Boone, T., & Smith, C. 2005,
“Inhibitory effect of intravesically applied botulinum toxin A in chronic
bladder inflammation”, J Urol, vol. 173, pp. 621-624.
Vercellini, P. 1997, “Endometriosis: what a pain it is”, Seminars in
Reproductive Endocrinology, vol. 15, pp. 251-261.
Verhaak, P. F. M., Kerssens, J. J., Dekker, J., Sorbi, M. J., & Bensing, J. M. 1998,
“Prevalence of chronic benign pain disorder among adults: a review of the
literature”, Pain, vol. 77, pp. 231-239.
Vliagoftis, H., Dimitriadou, V., Boucher, W., Rozniecki, J. J., Correia, I., Raam,
S., & Theoharides, T. C. 1992, “Estradiol augments while tamoxifen inhibits
rat mast cell secretion”, Int.Arch.Allergy Immunol., no. 4, pp. 398-409.
Vrinten, D., Kalkman, C., Adan, R., & Gispen, W. 2001, “Neuropathic pain: a
possible role for the melanocortin system?”, European Journal of
Pharmacology, vol. 429, pp. 61-69.
Wabner, C. L. & Pak, C. Y. C. 1993, “Effect of orange juice consumption on
urinary stone risk factors”, Journal of Urology, vol. 149, pp. 1405-1408.
Wallack, H., Lome, L. G., & Presman, D. 1975, “Management of interstitial
cystitis with ileocecocystoplasty”, Urology, vol. 5, no. 1, pp. 51-55.
Walsh, A. 1976, “Benzydamine: a new weapon in the treatment of interstitial
cystitis”, Trans.Am.Assoc Genitourin.Surg., vol. 68, pp. 43-44.
Walsh, A. 1977, “Interstitial cystitis. Observations on diagnosis and on treatment with anti-inflammatory drugs, particularly benzydamine”, Eur.Urol.,
vol. 3, no. 4, pp. 216-217.
Walsh, A. 1978, “Interstitial cystitis,” in Campbell's Urology, 4th edn, J. H.
Harrison et al., eds., W. B. Saunders Company, Philadelphia, pp. 693-707.
Walsh, A. 1985, “Cystolysis (supra-trigonal denervation) for intractable interstitial cystitis”, Urologists' Correspondence Club p. 142.
Warren, J. W. 1994, “Interstitial cystitis as an infectious disease”,
Urol.Clin.North Am., vol. 21, no. 1, pp. 31-39.
Warren, J. W., Horne, L. M., Hebel, J. R., Marvel, R. P., Keay, S. K., & Chai, T.
C. 2000, “Pilot study of sequential oral antibiotics for the treatment of
interstitial cystitis”, J Urol., vol. 163, no. 6, pp. 1685-1688.
Warren, J. W., Jackson, T. L., Langenberg, P., Meyers, D. J., & Xu, J. 2004,
“Prevalence of interstitial cystitis in first-degree relatives of patients with
interstitial cystitis”, Urology, vol. 63, no. 1, pp. 17-21.
Warren, J. W., Keay, S. K., Meyers, D., & Xu, J. 2001, “Concordance of interstitial cystitis in monozygotic and dizygotic twin pairs”, Urology, vol. 57, no.
6 Suppl 1, pp. 22-25.
Waxman, J. A., Sulak, P. J., & Kuehl, T. J. 1998, “Cystoscopic findings consistent with interstitial cystitis in normal women undergoing tubal ligation”, J
Urol., vol. 160, no. 5, pp. 1663-1667.
Weaver, R. G., Dougherty, T. F., & Natoli, C. A. 1963, “Recent concepts of
interstitial cystitis”, J Urol., vol. 89, pp. 377-383.
Webster, G. D. 1993, “Doctor's forum”, ICA Update p. summer.
Webster, G. D., MacDiarmid, S. A., Timmons, S. L., & et.al. 1992, “Impact of
urinary diversion procedures in the treatment of interstitial cystitis and
chronic bladder pain”, Neurourol Urodyn, vol. 11, p. 417.
Webster, G. D. & Maggio, M. I. 1989, “The management of chronic interstitial
cystitis by substitution cystoplasty”, J Urol., vol. 141, no. 2, pp. 287-291.
Wei, D. C., Politano, V. A., Selzer, M. G., & Lokeshwar, V. B. 2000, “The association of elevated urinary total to sulfated glycosaminoglycan ratio and high
molecular mass hyaluronic acid with interstitial cystitis”, J Urol., vol. 163,
no. 5, pp. 1577-1583.
AL
Teichman, J. M., Nielsen-Omeis, B. J., & McIver, B. D. 1997, “Modified urodynamics for interstitial cystitis”, Tech.Urol., vol. 3, no. 2, pp. 65-68.
Teichman, J. M., Thompson, I. M., & Taichman, N. S. 2000, “Joseph Parrish,
tic doloureux of the bladder and interstitial cystitis”, J Urol., vol. 164, no. 5,
pp. 1473-1475.
Theoharides, T. C. 1994, “Hydroxyzine in the treatment of interstitial cystitis”,
Urol.Clin.North Am., vol. 21, no. 1, pp. 113-119.
Theoharides, T. C. 2004, “Panic disorder, interstitial cystitis, and mast cells”,
J.Clin.Psychopharmacol., vol. 24, no. 4, pp. 361-364.
Theoharides, T. C. & Cochrane, D. E. 2004, “Critical role of mast cells in
inflammatory diseases and the effect of acute stress”, J.Neuroimmunol., vol.
146, no. 1-2, pp. 1-12.
Theoharides, T. C., Kempuraj, D., & Sant, G. R. 2001, “Mast cell involvement
in interstitial cystitis: a review of human and experimental evidence”,
Urology, vol. 57, no. 6 Suppl 1, pp. 47-55.
Theoharides, T. C. & Sant, G. R. 1991, “Bladder mast cell activation in interstitial cystitis”, Semin.Urol., vol. 9, no. 2, pp. 74-87.
Theoharides, T. C. & Sant, G. R. 1997b, “Hydroxyzine therapy for interstitial
cystitis”, Urology, vol. 49, no. 5A Suppl, pp. 108-110.
Theoharides, T. C. & Sant, G. R. 1997a, “Hydroxyzine for symptomatic relief
of interstitial cystitis symptoms,” in Interstitial Cystitis, G. R. Sant, ed.,
Lippincott-Raven, Philadelphia, pp. 241-246.
Theoharides, T. C., Sant, G. R., El Mansoury, M., Letourneau, R., Ucci, A. A.,
Jr., & Meares, E. M., Jr. 1995, “Activation of bladder mast cells in interstitial
cystitis: a light and electron microscopic study”, J Urol., vol. 153, no. 3 Pt 1,
pp. 629-636.
Thilagarajah, R., Witherow, R. O., & Walker, M. M. 2001, “Oral cimetidine
gives effective symptom relief in painful bladder disease: a prospective, randomized, double-blind placebo-controlled trial”, BJU International, vol. 87,
pp. 207-212.
Tincello, D. & Walker, A. 2005, “Interstitial cystitis in the UK: results of a questionnaire survey of members of the interstitial cystitis support group”, Eur
J Obstet Gynecol Reprod Biol, vol. 118, no. 1, pp. 91-95.
Tissot, W. D., Diokno, A. C., & Peters, K. M. 2004, “A referral center's experience with transitional cell carcinoma misdiagnosed as interstitial cystitis”,
J.Urol, vol. 172, no. 2, pp. 478-480.
Tomaszewski, J. E., Landis, J. R., Brensinger, C., Hardy, C., & et.al. 1999,
“Baseline associations among pathologic features and patient symptoms in
the national interstitial cystitis data base”, Journal of Urology, vol. 161 S, p.
28.
Tomaszewski, J. E., Landis, J. R., Russack, V., Williams, T. M., Wang, L. P.,
Hardy, C., Brensinger, C., Matthews, Y. L., Abele, S. T., Kusek, J. W., &
Nyberg, L. M. 2001, “Biopsy features are associated with primary symptoms
in interstitial cystitis: results from the interstitial cystitis database study”,
Urology, vol. 57, no. 6 Suppl 1, pp. 67-81.
Toren, P. & Norman, R. 2005, “Cyclophosphamide
hosphamide induced hemorrhagic cystitis successfully treated with pentosanpolysulfate”, J Urol, vol. 173, p. 103.
Trelstad, R. L. 1985, “Glycosaminoglycans: Mortar, matrix, mentor”, Lab
Invest, vol. 53, pp. 1-4.
Trinka, P. J., Stanley, B. K., Noble, M. J., & et.al. 1993, “Mast-cell syndrome: A
relative contraindication for continent urinary diversion”, Journal of
Urology, vol. 149, p. 506A.
Truong, L. D., Ostrowski, M. L., & Wheeler, T. M. 1994, “Tamm-horsfall protein in bladder tissue”, American Journal of Surgical Pathology, vol. 18, pp.
615-622.
Turner, J. A., Deyo, R. A., Loeser, J. D., & et.al. 1994, “The importance of placebo effects in pain treatment and research”, JAMA, vol. 271, pp. 1609-1614.
Ueda, T., Tamaki, M., Ogawa, O., Yamauchi, T., & Yoshimura, N. 2000,
“Improvement of interstitial cystitis symptoms and problems that developed during treatment with oral IPD-1151T”, J Urol., vol. 164, no. 6, pp.
1917-1920.
Ueda, T., Tamaki, M., Ogawa, O., & Yoshimura, N. 2002, “Over expression of
platelet-derived endothelial cell growth factor/thymidine phosphorylase in
patients with interstitial cystitis and bladder carcinoma”, J Urol., vol. 167,
no. 1, pp. 347-351.
Uehling, D. T., Kelley, E., Hopkins, J., & et.al. 1988, “Urinary glycosaminoglycan levels following induced cystitis in monkeys”, Journal of Urology, vol.
139, pp. 1103-1105.
Urban, L., Nagy, I., & Bevan, S. 2002, “Chronic neuropathic pain: pathomechanism and pharmacology”, Drug Develpment Research, vol. 54, pp. 159166.
Utz, D. C. & Zincke, H. 1974, “The masquerade of bladder cancer in situ as
interstitial cystitis”, J Urol., vol. 111, no. 2, pp. 160-161.
Utz, D. C. & Zincke, H. 1973, “The masquerade of bladder cancer in situ as
interstitial cystitis”, Trans.Am.Assoc Genitourin.Surg., vol. 65, pp. 64-65.
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
SECTION III
56
AL
basement membrane in interstitial cystitis”, J Urol., vol. 154, no. 3, pp. 12221226.
Wishard, WN., Jr., Nourse, M. H., & Mertz, JH. 1957, “Use of clorpactin WCS
90 for relief of symptoms due to interstitial cystitis”, J Urol., vol. 77, no. 3,
pp. 420-423.
Worth, P. H. 1980, “The treatment of interstitial cystitis by cystolysis with
observations on cystoplasty. A review after 7 years”, Br J Urol., vol. 52, no.
3, p. 232.
Worth, P. H. & Turner-Warwick, R. 1973, “The treatment of interstitial cystitis by cystolysis with observations on cystoplasty”, Br J Urol., vol. 45, no. 1,
pp. 65-71.
Worth, P. H. L. & Turner-Warwick, R. 1972, “Interstitial cystitis (letter)”, BMJ,
vol. April 8, pp. 111-112.
Wyndaele, J. J. 1998, “The normal pattern of perception of bladder filling during cystometry studied in 38 young healthy volunteers”, Journal of Urology,
vol. 160, pp. 479-481.
Yamada, T., Murayama, T., Mita, H., & Akiyama, K. 2000, “Subtypes of bladder mast cells in interstitial cystitis”, Int.J.Urol., vol. 7, no. 8, pp. 292-297.
Yilmaz, U., Liu, Y. W., Rothman, I., Lee, J. C., Yang, C. C., & Berger, R. E. 2004,
“Intravesical potassium chloride sensitivity test in men with chronic pelvic
pain syndrome”, J.Urol., vol. 172, no. 2, pp. 548-550.
Yoshimura, N. & de Groat, W. C. 1999, “Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation”,
Journal of Neuroscience, vol. 19, pp. 4644-4653.
Yun, S. K., Laub, D. J., Weese, D. L., Lad, P. M., Leach, G. E., & Zimmern, P. E.
1992, “Stimulated release of urine histamine in interstitial cystitis”, J Urol.,
vol. 148, no. 4, pp. 1145-1148.
Zaslau, S., Riggs, D. R., Jackson, B. J., Adkins, F. C., John, C. C., Kandzari, S. J.,
& McFadden, D. W. 2004, “In vitro effects of pentosan polysulfate against
malignant breast cells”, Am.J.Surg., vol. 188, no. 5, pp. 589-592.
Zeidman, E. J., Helfrick, B., Pollard, C., & Thompson, I. M. 1994, “Bacillus
Calmette-Guerin immunotherapy for re
refractory interstitial cystitis”,
Urology, vol. 43, no. 1, pp. 121-124.
Zermann, D.-H., Ishigooka, M., Doggweiler, R., & Schmidt, R. A. 1999,
“Neurourological insights into the etiology of genitourinary pain in men”,
Journal of Urology, vol. 161, pp. 903-908.
Zermann, D. H., Ishigooka, M., Doggweiler, R., & Schmidt, R. A. 1998,
“Postoperative chronic pain and bladder dysfunction: windup and neuronal plasticity -- do we need a more neurourological approach in pelvic
surgery?”, Journal of Urology, vol. 160, pp. 102-105.
Zuraw, B. L., Sugimoto, S., Parsons, C. L., Hugli, T., Lotz, M., & Koziol, J. 1994,
“Activation of urinary kallikrein in patients with interstitial cystitis”, J Urol.,
vol. 152, no. 3, pp. 874-878.
PR
SA O
M PE
PL R
E TY
C O
O F
N E
TE L
N SE
T V
- N IE
O R
T
FI
N
Wein, A. J. & Broderick, G. A. 1994, “Interstitial cystitis. Current and future
approaches to diagnosis and treatment”, Urol.Clin.North Am., vol. 21, no.
1, pp. 153-161.
Wein, A., Hanno, P. M., & Gillenwater, J. Y. 1990, “Interstitial Cystitis: an introduction to the problem,” in Interstitial Cystitis, P. M. Hanno et al., eds.,
Springer-Verlag, London, pp. 3-15.
Weisman, M. H., McDanald, E. C., & Wilson, C. B. 1981, “Studies of the
pathogenesis of interstitial cystitis, obstructive uropathy, and intestinal
malabsorption in a patient with systemic lupus erythematosus”, Am.J.Med.,
vol. 70, no. 4, pp. 875-881.
Weiss, J. M. 2001, “Pelvic floor myofascial trigger points: manual therapy for
interstitial cystitis and the urgency-frequency syndrome”, J Urol., vol. 166,
no. 6, pp. 2226-2231.
Weiss, J. P. & Neville, E. C. 1989, “Hyperbaric oxygen: Primary treatment of
radiation-induced hemorrhagic cystitis”, Journal of Urology, vol. 142, pp.
43-45.
Weiss, J. P., Wein, A. J., & Hanno, P. M. 1984, “Sigmoidocystoplasty to augment
bladder capacity”, Surg Gynecol Obstet, vol. 159, pp. 377-380.
Weissman, M. M., Gross, R., Fyer, A., Heiman, G. A., Gameroff, M. J., Hodge,
S. E., Kaufman, D., Kaplan, S. A., & Wickramaratne, P. J. 2004, “Interstitial
cystitis and panic disorder: a potential genetic syndrome”,
Arch.Gen.Psychiatry, vol. 61, no. 3, pp. 273-279.
Wesselmann, U. 2001, “Interstitial cystitis: a chronic visceral pain syndrome”,
Urology, vol. 57, no. 6 Suppl 1, pp. 32-39.
Wesselmann, U., Burnett, A. L., & Heinberg, L. J. 1997, “The urogenital and
rectal pain syndromes”, Pain, vol. 73, pp. 269-294.
Wessely, S. & White, P. 2004, “There is only one functional somatic syndrome”,
British Journal of Psychiatry, vol. 185, pp. 95-96.
Whiteside, J. & Falcone, T. 2003, “Endometriosis-related pelvic pain: what is
the evidence?”, Clin.Obstet.Gynecol., vol. 46, no. 4, pp. 824-830.
Whitmore, K. E. 1994, “Self-care regimens for patients with interstitial cystitis”, Urol.Clin.North Am., vol. 21, no. 1, pp. 121-130.
Whitmore, K. E., Payne, C. K., Diokno, A. C., & Lukban, J. C. 2003, “Sacral
neuromodulation in patients with interstitial
itial cystitis: a multicenter clinical
trial”, Int.Urogynecol.J Pelvic.Floor.Dysfunct., vol. 14, no. 5, pp. 305-308.
Wiesenfeld-Hallin, Z. & Xu, X. 2001, “Neuropeptides in neuropathic and
inflammatory pain with special emphasis on cholecystokinin and galanin”,
European Journal of Pharmacology, vol. 429, pp. 49-59.
Wilkins, E. G., Payne, S. R., Pead, P. J., Moss, S. T., & Maskell, R. M. 1989,
“Interstitial cystitis and the urethral syndrome: a possible answer”, Br J
Urol., vol. 64, no. 1, pp. 39-44.
Wilson, C. B., Leopard, J., Nakamura, R. M., Cheresh, D. A., Stein, P. C., &
Parsons, C. L. 1995, “Selective type IV collagen defects in the urothelial
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CHAPTER 10
Painful Bladder Syndrome/Interstitial Cystitis and Related Disorders