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Abstract
Introduction
Interstitial cystitis (IC) is a chronic inflammatory disorder
of the bladder that is notoriously difficult to manage
and can result in considerable morbidity. It can cause
symptoms of frequency and urgency, with pain as a
predominant feature in one or more regions of the pelvis
typically in the bladder, vagina or perineum leading to a
poor quality of life.
Correspondence: Matthew Parsons, Consultant,
Department of Urogynaecology, Birmingham Womens
Hospital, Metchley Park Road, Edgbaston, Birmingham
B15 2TG, UK. Email: matthew.parsons@bwhct.nhs.uk
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Incidence
Women between the ages of 40 and 60 years are most
commonly affected. The condition occurs more frequently
in Caucasians and there is a 9:1 female predominance. 3
Reported prevalence rates for this condition vary widely
as there is no universally accepted definition.
In the Nurses Health Study I and II (n = 184,583) the
prevalence of IC was 5267/100,000, with no substantial
age variation.4 Although the results must be interpreted
in the light of the higher proportion of Caucasians in
this study than the background population, this is 50%
higher than was previously reported in the United States,
and three times greater than in European studies. In a
Finnish study of 2000 participants randomly selected
from the population register, the prevalence of symptoms
corresponding to probable IC was 450/100,000 (95% CI
100800), which is an order of magnitude higher again. 5
Aetiology
A brief summary is presented of some hypotheses relating
to the management and investigation of IC.6
Infection
An infective cause for IC has been postulated repeatedly
since 1915 (see under Cystoscopy, below). However,
according to the criteria of the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK), 3
infection is a cause for the exclusion of a diagnosis of IC,
and an infective agent has not been consistently identified.
Interstitial cystitis
Pelvic examination
Urotoxins
Urinary toxins and allergens have been postulated to be
involved in the deficiency of the GAG layer.
Hypoxia
Vascular, hormonal or toxic factors leading to hypoxia
of the bladder wall could affect the integrity of the GAG
layer. A reduced blood flow in the sub-urothelial layers
(but not deeper layers) has been seen in women with IC.
Clinical features
The symptom complex that should define IC is controversial. Typical symptoms include frequency, urgency, dysuria,
and lower abdominal, bladder, vaginal, urethral or perineal
pain, in the absence of bacterial cystitis. Voiding often
relieves the suprapubic discomfort, and drinking alcoholand caffeine-containing drinks frequently exacerbates the
pain. In a UK-based postal questionnaire survey, 64% of
respondents described daily pain when symptoms were at
their worst, and 37% described daily pain at the time of
survey. Most reported frequency, urgency and nocturia.7
Sixty-seven per cent reported a considerable impact
or more on their lifestyle and 46% reported moderate
depression or worse. Forty-nine per cent reported at least
considerable difficulties with sexual intercourse.
Incontinence tends not to be a major feature of IC,
although 14% of IC patients have evidence of detrusor
overactivity on subtracted cystometry.8 What is not clear
is whether the presenting complaint affects the likely
outcome of treatment.9 At a consensus workshop in Kyoto,
attendees were of the opinion that pelvic pain, urgency
and urinary frequency are necessary for IC to be a differential diagnosis.10
Pain typically occurs in the pelvic area in the bladder,
vagina, urethra, rectum or perineum and must be
Urine studies
Urinalysis is usually normal but haematuria may be
present. Urine culture is essential to exclude simple
urinary tract infection, as well as atypical infections,
such as Ureaplasma urealyticum, Mycoplasma hominis or
Chlamydia trachomatis.
Urine cytology is recommended if haematuria is
present, or if there are risk factors for bladder cancer
(smoking, age, family history, occupational exposure to
certain industrial chemicals such as aromatic amines). In
a study of 128 women with irritative bladder symptoms,
and a total of 202 urine specimens, no positive cytology
nor transitional cell carcinomas were found in women
without haematuria.12 The cost-effectiveness of urinary
cytology in women without haematuria or risk factors is
therefore questionable.
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Interstitial cystitis
Urine markers
Certain markers are significantly increased in IC,
including anti-proliferative factor, epidermal growth factor,
insulin-like growth factor (IGF) binding protein-3 and
interleukin (IL)-6. Anti-proliferative factor is the most
likely candidate to become a diagnostic test, as it gives the
least overlap between the IC and control groups.20
Luminal nitric oxide (NO) can be used as a marker
to differentiate inflammation, which defines IC, from
urgency, frequency, nocturia and pain due to noninflammatory disorders, such as outflow obstruction
and neurogenic dysfunction.21 There is a nearly 20-fold
increase in mean bladder NO concentration in patients
with IC compared with those with detrusor overactivity,
outflow obstruction or sensory urgency, and compared
with asymptomatic controls. Further study has shown a
statistically significant correlation between changes in
symptom/problem scores and changes in luminal bladder
NO in individual patients, which suggests that NO could
be used not only to measure inflammation but also as an
objective evaluation of treatment response.22
Voiding diary
The voiding diary is an important tool in the investigation of lower urinary tract symptoms.23 It may range in
complexity from simple records of intake and output to
more complex diaries that include symptoms and incontinence episodes, and pad use, to facilitate history taking
about the degree of frequency, nocturia and volumes
voided at each episode. They are useful in the identification of polydipsia and polyuria as a cause of urinary
frequency.
In order for a voiding diary to have value, it must be
completed correctly. If the diary is too long then compliance is likely to be poor. Day-to-day variability may
compromise diaries that cover only one or two days,
and so a three-day diary has been suggested as optimal,
although others advocate a single-day diary. 24,25
Patients with IC have lower volumes at first sensation
to void and lower functional capacity than those without
the condition.26 Maximum voided volume is usually taken
to represent functional capacity. A significant positive
correlation has been found between cystometric bladder
capacity and maximum voided volume as recorded in a
home diary (rr = 0.4938, P < 0.01), which establishes the
validity of the latter.27 It is therefore usual to see women
with IC having frequent voids of small volume.
Urodynamics
The role of urodynamics is to rule out alternative
pathology, such as obstructed voiding or detrusor overactivity, rather than to provide a positive diagnosis of IC.
The relationship of uninhibited bladder contractions
with IC or painful bladder syndrome is not clear. In a
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Cystoscopy
The pursuit of a definition and diagnosis of IC began in
1887, when Skene described the disease as an inflammation of the bladder that destroyed the mucosa and
extended to the muscular parietes. In 1915 Hunner
described an ulcer. Glomerulations small, discrete,
purple haemorrhages of the bladder mucosa that are often
found in IC patients were first described in 1949.2
The purpose of cystoscopy is the exclusion of local,
intravesical abnormalities. The majority of patients with
IC have a urothelium that appears normal. In a study
of 196 women suffering from frequency, urgency and/or
bladder pain, patients with bladder pain at full bladder
and a positive KCl test had only a 45.2% chance of having
the characteristic appearances of the urothelium at
cystoscopy (see Figure 1). 30
The decision for cystoscopy, then, is frequently based
on the presence or absence of risk factors for conditions
such as bladder cancer. Since 1% of IC patients in a tertiary unit in the United States were eventually diagnosed
with transitional cell carcinoma of the bladder, some
authorities advocate cystoscopy as a mandatory investigation. 32,33
Rigid cystoscopy, under general or regional anaesthesia, is preferred to facilitate biopsy glycine should
be used as a filling medium if diathermy is to be used
for coagulation, although saline is adequate where
Versapoint (Bipolar Electrosurgery System) is available.
Infusion height should be approximately 80 cm above the
Interstitial cystitis
Diagnosis
There have been three major conferences in recent years
to try to establish a consensus on the diagnosis of IC:
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Interstitial cystitis
Terminology
All three conferences debated their dissatisfaction with
the term interstitial cystitis. In Kyoto the suggestion
was that the term chronic pelvic pain syndrome
should be used, but this was countered by the argument
that some women respond to anticholinergics while
others do not, and that this therefore distinguishes an
overactive bladder from IC. The compromise IC as
part of a chronic pelvic pain syndrome (IC/CPPS) was
unanimously agreed. In Virginia there was disagreement
as to whether the term IC detracts from the diagnosis,
but it was felt that, as IC is prevalent in the medical
literature, dropping it would be too confusing. Rather,
it should be coupled with chronic pelvic pain (IC/
CPPB) and eventually IC dropped. In Copenhagen, the
definition provided by the International Continence
Society was adhered to more closely: of painful bladder
syndrome (PBS) as 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.1
Management
Management options can seem as bewildering as the
aetiology to those clinicians trying to manage patients
with IC. Management begins with the first visit and
assessment, by acknowledging and validating the pain,
and setting patient expectations. 39 A wide range of
treatments are frequently offered, but in the UK drugs
of proven efficacy are typically offered to only a third or
less of patients. These include cimetidine (offered to 36%
of patients in one survey); antihistamines (5%); pentosan
polysulfate (12%); dimethyl sulfoxide (DMSO) (33%);
and anticonvulsants (2%).7 The five most commonly used
therapies in the United States have been reported to be
cystoscopy and hydrodistension, amitriptyline, phenazopyridine (a urinary tract analgesic not available in the
UK), special diet and intravesical heparin.40 A total of 183
different types of therapy were recorded!
Pharmacotherapy in IC is based on three principles:
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Behavioural treatments
A major part of the management of patients with IC is
behavioural and non-pharmacological: physical therapy,
avoidance of flare-inducing foods, bladder training,
and stress management techniques can supplement
pharmacological treatment and improve clinical
response.41
Patients need to become involved in their management
and should be offered advice about accurate educational
resources. The Internet provides an easy way to access
a support group42,43 and gain valuable information, for
example regarding diet (dietary modification is usually
recommended, although there is little evidence from
randomized trials as to which foods are best avoided).
Avoiding foods with a high acidity or high potassium
content is desirable (see Table 1).
Hydrodistension
Cystoscopy with hydrodistension is the most commonly
performed diagnostic test and procedure and is thought
to work by disrupting bladder neuronal pathways and thus
pain transmission. The benefits are short-lived: in one
casecontrol series the benefits of hydrodistension lasted
a mean of only two months.44 It is therefore no longer
recommended.
Pharmacological treatments
Dimethyl sulfoxide (DMSO) and intravesical heparin
DMSO, a by-product of the wood industry, has been in
use as a commercial solvent since 1953. DMSO reduces
inflammation by several mechanisms. It is an antioxidant
and a scavenger of the free radicals that gather at the site
of injury; DMSO also stabilizes membranes and slows or
stops leakage from injured cells, and so may be useful in
restoring the GAG layer.
In a study evaluating the effectiveness of DMSO in the
treatment of cystoscopy-positive IC, patients were randomly allocated to receive either 50% DMSO or placebo
(saline) intravesically every two weeks for two sessions of
four treatments each. Subjectively, 53% of DMSO-treated
patients were markedly improved, compared with 18% in
the placebo group. Objectively, 93% of the DMSO group
were improved versus 35% in the placebo group.45 While
there were no significant side-effects, many patients complained of garlic halitus. In 25 patients followed for 12
months the relapse rate was 59%.
Heparin is a GAG that may afford protection to
the urothelium and reduce the relapse rate. It is better
tolerated than DMSO and does not produce garlic
halitus. It is not associated with coagulation anomalies
when administered intravesically, and may be useful in
up to 56% of patients.46 It also produces a significant
reduction in the relapse rate among patients who respond
to DMSO.47
Interstitial cystitis
Permitted
Best avoided
Beverages
Breads
Cereals
Fats
Soups
Meat, fish,
poultry
Dairy
Vegetables
Beans
Fruits
Sweets
Dressings,
herbs and
spices
Nuts
Breakfast cereals
Sodium pentosanpolysulfate
Sodium pentosanpolysulfate is chemically and structurally
similar to naturally occurring GAGs that are produced
by, and form a protective layer covering, the epithelium
of the urinary tract. It inhibits complement reactions in
inflammatory processes.48 It is the only oral agent used to
treat IC that has been rigorously investigated in doubleblind trials.
In a randomized, prospective, double-blind, placebocontrolled study conducted in 148 patients, 32% of the
group on sodium pentosanpolysulfate (100 mg three times
daily) showed significant improvement, compared with
16% on placebo ((P
P = 0.01). They also experienced a significant decrease in pain and urgency ((P
P = 0.04 and 0.01,
respectively).49
Further, in a randomized, double-blind, doubledummy, parallel-group, multicentre, 32-week study of
380 adults examining 300 mg, 600 mg and 900 mg doses
of sodium pentosanpolysulfate, improvement was not
dose dependent. The duration of therapy appeared more
important. 50
Hyaluronic acid and chondroitin sulfate
Hyaluronic acid is an important GAG that is present
throughout the body in connective tissues. In 25 patients
with the characteristic picture of IC and refractory
to other medical treatments, intravesical hyaluronic
acid produced a positive response rate of 56% at week
4, increasing to 71% by week 12. This response was
maintained until week 20; beyond week 24 there appeared
to be a moderate decrease in the effectiveness of the
medication. 51 There was no significant toxicity attributable to the presence of hyaluronic acid in the bladder. In
a small Danish follow-up study, monthly instillation of
sodium hyaluronate solution over three years gave benefit
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Interstitial cystitis
References
Amitriptyline
Amitriptyline is frequently used in pain management. 59
Anecdotal experiences with the tricyclic class of antidepressants suggest that amitriptyline may be an effective
treatment modality in non-ulcerative IC.60 It was shown to
be effective in a small placebo-controlled study.61
Antihistamines
Increased numbers of activated mast cells have been
documented close to nerve endings containing substance
P in the bladders of patients with IC. Bladder mast cells
can be activated by carbachol, while hydroxyzine reduces
carbachol-induced serotonin release from rat bladder.62 In
an open-label case series of patients treated by their local
doctor, a 40% reduction in symptom scores was reported.
This rose to 55% in patients with a history of allergies,
suggesting that hydroxyzine is a useful drug for the
symptomatic treatment of IC, especially in patients with
documented allergies or evidence of bladder mast cell
activation.63 However, larger randomized studies would be
required to support a strong recommendation.
Surgery
Where other treatments fail and symptom severity is such
that the patients quality of life is very poor, a urological
opinion should be sought and reconstructive surgery
considered. Available options include partial cystectomy,
augmentation cystoplasty, and urinary diversion with or
without cystectomy.
Conclusions
IC is a chronic, disabling condition affecting predominantly women (Box 2). The aetiology is uncertain,
but almost certainly multi-modal. It presents with a
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