EFFECT OF INTRAVESICAL HYALURONIC ACID TREATMENT ON

Acta Medica Mediterranea, 2014, 30: 1177
EFFECT OF INTRAVESICAL HYALURONIC ACID TREATMENT ON BLADDER PAIN
SYNDROME/INTERSTITIAL CYSTITIS
FETULLAH GEVHER1, MUSTAFA BILAL TUNA1, ÇETIN DEMIRDAĞ1, ÖNDER KARA2, OKTAY DEMIRKESEN3
1
Istanbul University, Cerrahpasa School of Medicine, Urology, Istanbul - 2Hacettepe University, School Of Medicine, Urology,
Ankara - 3Istanbul University, Cerrahpasa School Of Medicine, Urology, Istanbul, Turkey
ABSTRACT
Purpose: Our study aims to evaluate the efficacy of hyaluronic acid (HA) on interstitial cystitis patients admitted to our clinic
with the diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC).
Material and methods: The pre- and post-treatment symptom scores the severity of symptoms, and cystoscopic and pathologic
findings of 23 patients diagnosed with BPS/IC were prospectively evaluated between 2009-2013. The O'Leary-Sant Interstitial
Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI) Scale, and Pelvic Pain and Urgency/Frequency Patient
Symptom Scale (PUFSS) were used as questionnaire forms. 40 mg HA was administered intravesically for 6 weeks. Results were
reviewed in patients who completed the treatment.
Results: Two patients discontinued the treatment, 21 patients were enrolled in the study. The mean age was 48 (33-78). 20
patients underwent cystoscopy surgery. While 8 of them showed nonspecific changes in the trigonum area, 12 had no pathologies.
While the mean ICSI score of the 21 patients who filled out the ICSI/ICPI and PUFSS questionnaire forms was 15.6 (12-20) pretreatment and 9.2 (1-18) post-treatment (p<0.01), the mean ICPI score was 13.1 (7-16) pre-treatment, and 7.8 (0-16) post-treatment
(p<0.01). The mean PUFSS score was 23.9 (14-35) pre-treatment, and 16.4 (5-31) post-treatment (p<0.01). While the mean PUF
symptom score was 16.1 (10-23) pre-treatment, and 10.9 (3-19) post-treatment (p<0.01), the mean PUF quality of life score was 7,8
(4-12) pre-treatment, and 5.5 (1-12) post-treatment (p<0.01). No side effects were found in the patients.
Conclusion: Intravesical HA therapy is a safe treatment option in the treatment of BPS/IC. While it has a certain degree of
efficacy, further prospective, randomized, placebo-controlled studies with a larger study population are required.
Key words: Cystitis, Interstitial, Glycosaminoglycans, Hyaluronic Acid.
Received May 18, 2014; Accepted September 02, 2014
Introduction
Bladder Pain Syndrome/Interstitial Cystitis
(BPS/IC) is a chronic intermittent clinical syndrome
characterized by a constellation of symptoms that
include bladder/pelvic pain associated with urinary
urgency, frequency and dysuria(1). There are cystoscopic and histologic features which are said to be
typical but in many cases the diagnosis is one of
exclusion in order to rule out specific causes such as
infection and malignancy.
The underlying pathophysiology of this disease
is still unknown. A loss of the glycosaminoglycans
(GAG) ‘’water-tight’’ function at the epithelial surface of the bladder, possibly due to an infective or
other inflammatory insult is thought to be important
as this exposes the bladder subepithelium to substances present in urine (normal substances such as
Na+, K+, H+, Cl- and abnormal substances such as
cytotoxic drugs and toxins)(2). Once these irritating
substances come into direct contact with the subepithelial layers, they are causing inflammation and
delayed healing of the damaged urothelial layer and
GAGs(3). This is also thought to be important along
with sensory nerve upregulation and enhanced mast
cell activation(4). The end result of this process is a
form of regional neuropathy that can have other
gynaecological and gastrointestinal manifestations as
well as pain and voiding symptoms(5).
Hyaluronic acid (HA) is a major mucopolysaccharide found widely in the epithelial, neural and
connective tissues. HA is used in different ways in
1178
the treatment of patients. It is used in certain orthopedic and ophthalmologic procedures(6,7); in cosmetic
regeneration and reconstruction tissue(8); and in vesicoureteral reflux(9). In urothelium it constitutes a protective barrier(10) and has an inhibitory action on mast
cell activation which is considered a crucial step in
the pathogenesis of BPS/IC(11). In light of these findings, the early repair of the GAG layer by HA might
avoid the chronic evolution of bladder inflammation.
The aim of this study was to determine whether
hyaluronic acid instillation had an impact on the urinary frequency, nocturia, life quality in patients diagnosed with BPS/ IC.
Material and methods
A total of 23 patients diagnosed with BPS/IC
between 2009-2013 were recruited for this open,
prospective, unblinded, uncontrolled study. All
patients were chosen from among patient who did
not benefit from the previous oral medication, life
behavioral changes and dietary recommendations.
Diagnosis was made based on criteria defined by
European Society for the Study of Interstitial
Cystitis criteria(1).
Patients were included in the study if they had
chronic pelvic pain, pressure, or discomfort, perceived to be related to the urinary bladder accompanied by at least one other urinary symptom, such as
persistent urge to void or frequency. Exclusion criteria included age under 18 years; pregnancy or
breastfeeding; vesical urethral pathologies (as
infective or actinic cystitis, neurogenic bladder, urethral diverticula, bladder or urethral cancer, urinary
stones, urge/ stress incontinence, pelvic prolapses)
or nonvesical pathologies (vaginitis, uterine, vaginal or cervical cancers, endometriosis) not related
to IC/BPS.
All patients undergone physical examination,
full blood count, urine analyses, urinary tract ultrasonography (USG), and urinary tuberculosis (TBC)
analyses. TBC analyses were made by EZN
(Ehrlich-Ziehl-Nielsen) staining and where possible
by adding the PCR (Polymerase Chain Reaction)
method. A 3-day voiding diary form was filled out
for each patient. 16 patients underwent urodynamic
evaluation. Cytologies and cytoscopic examination
were carried out for patients who had hematuria in
urine analyses and bladder wall thickening in ultrasound images. Concurrent “hydrodistention+bladder
capacity measurement” was performed during cystoscopy, and biopsy samples were received from sus-
Fetullah Gevher, Mustafa Bilal Tuna et Al
picious areas. This procedure were performed under
general anesthesia in dorsal lithotomy position. The
saline was put 70-80 cm above the suprapubic area
and the bladder was filled passively with saline. The
bladder was distended for 1-5 minutes when the
urine stream to the bladder was stopped. Then the
bladder was slowly emptied, and the total drained
volume was recorded as the maximum bladder
capacity. The bladder was refilled to perceive
changes in the bladder surface (glomerulation).
Cold-cup biopsy samples were obtained from
patients who had suspicious areas after hydrodistention: 1 sample from the suspicious area and 1
sample randomly from any area of the bladder.
The O'Leary-Sant (OLS) Interstitial Cystitis
Symptom Index (ICSI) and Interstitial Cystitis
Problem Index (ICPI) scale, and Pelvic Pain and
Urgency/Frequency Patient Symptom Scale
(PUFSS), (overall PUFSS score, PUFSS symptom
score, and PUFSS quality of life score) forms were
filled out for each patient both pre-treatment and 15
days after post-treatment(12,13).
Complete Urine Analysis (CUA) was performed before each instillation, and urine culture
and antibiogram was performed in the event of any
findings of infection in CUA. Appropriate antibiotic
treatment was performed in the event of urinary
tract enfection, and instillation was delayed. A 8F
silicon catheter was inserted to empty the bladder,
40mg HA 1.6% (800 mg/50 ml) was dilueted in
saline and was administered intravesically as a 50cc
solution under sterile urine conditions weekly for
six weeks. The patients were instructed to retain the
hyaluronic acid in their bladders at least for 2 hours
after the instillation. 15 days after the final administration, the voiding diary, the ICSI and ICPI scales
and PUFSS forms were filled out again in order to
asses the response to therapy.
All patients provided written informed consent
prior the treatment and this study was approved by
the ethics committee of our hospital.
The SPSS® software was used for statistical
analysis. The variables were compared using the
Wilcoxon rank sum test. Data were expressed as
mean ± standard deviation. p<0.05 was considered
to be statistically significant.
Results
Of the 23 patients diagnosed with BPS/IC 2
patients (8.7%) discontinued the treatment after 2
sessions claiming to have gained no benefits from
Effect of intravesical hyaluronic acid treatment on bladder pain syndrome/interstitial cystitis
the treatment, these two patients were excluded
from the study and 21 patients were enrolled in the
study. Patients characteristics are shown in Table 1.
None of the patients had any bacteria in their urinary cultures.
Patients, n
21
Sex (M/F)
19-Feb
Age, years ± SD
48 ±12.19 (33-78)
BMI, kg/m2 ± SD
25.2± 3.2
Parity, n
2.5
Menopausal, n (%)
11 (52%)
Time since BPS/IC
diagnosis, years
4.7
Table 1: Patients characteristics (mean values).
BMI: body mass index; BPS/IC: Bladder pain syndrome/
Interstitial cystitis; SD: standard deviation
Pretreatment
questionnaire
scores, mean
(SD)
Post-treatment
questionnaire
scores, mean
(SD)
p value
(t test)
ICSI
15.6±4.3 (12-20)
9.2 ±4.0 (1-18)
0.0005
ICPI
13.1 ± 2.19 (716)
7.8 ± 1.83 (0-16)
0.0065
Overall PUFSS scores
23.9±3.14 (1435)
16.4 ±2.62 (5-31)
0.0006
16.1 ±2.68 (1010.9 ±2.30 (3-19)
23)
0.0066
7,8 ±1.05 (4-12)
5.5±0.83 (1-12)
0.0078
Day time
10.5 ±1.73 (615)
7.5 ±0.92 (5-15)
0.0001
Night time
3±1.21 (1-7)
1.9±0.89 (0-5)
0.0001
117.3±±39.1
(78-153)
153±±37.4 (98186)
0.0056
Mean PUFSS symptom score
Mean PUFSS quality of life score
Number of voids
Mean urine volume
per void
Table 2: Results from the patient questionnaires pre and
post treatment.
ICPI: Interstitial Cystitis Problem Index; ICSI: Interstitial
Cystitis Symptom Index
PUFSS: Pelvic Pain and Urgency/Frequency Patient Symptom
Scale; SD: standard deviation
All of the patients underwent cystoscopy. Of
these two had bladder wall thickening in the USG
(9.5%). During cystoscopy 8 of 21 patients showed
nonspecific changes in the trigonum area(38%), 13
had no pathologic findings. After hydrodistantion
glomerulations were observed in 11 of all patients
(52%). Biopsy samples were obtained from suspicious
areas in 9 patients who underwent cystoscopy (43%).
“Partial desquamation of the superficial epithelium,
chronic active cystitis, mononuclear cellular infiltra-
1179
tion” were found in 6 of them (29%). Three patients
had no specific pathologic abnormalities.
Thirteen patients had hematuria (62%). All of
these patients underwent urine cytologie analysis.
Of these 12 had no pathological findings in their
cytology results. Atypical cells were found in 1
patient. Biopsy was performed for this patient and
no specific pathologic abnormalities were found.
16 patients underwent urodynamic evaluation
(76%). Three of them had involuntary bladder contractions (18.7%), 13 had normal detrusor activity.
Voiding diaries were kept for all patients. The
mean pretreatment day time voiding frequency and
mean nocturia frequency decreased from 10.5 (615) to 7.5 (5-15) (p<0.01) and from 3 (1-10) to 1.9
(p<0.01) respectively. Mean urine volume per void
increased from 117.3 to 153 ml (p<0.01).
Results from the patient questionnaires are
shown in table 2. Pre and post-treatment mean ICSI
score was 15.6 (12-20) and 9.2 (1-18) respectively
(p<0.01). The mean pre-treatment ICPI score was
13.1 (7-16) and post-treatment 7.8 (0-16) (p<0.01).
When analyzing the mean values of the overall
PUFSS score, PUFSS symptom score, and PUFSS
quality of life score, a statistically significant
change after treatment was reported compared with
baseline. The overall PUFSS mean values
decreased from 23.9 (14-35) to 16.4 (5-31)
(P<0.01), mean PUFSS symptom score decreased
from 16.1 (10-23) to 10.9 (3-19) (P<0.01) and the
mean PUFSS quality of life score decreased from
7,8 (4-12) to 5.5 (1-12) (P<0.01).
The mean follow up was 4 months (range 2–7
months) from the end of the instillation protocol.
No cases of intolerance, side effects or complications were observed.
Discussion
BPS/IC is a chronic bladder condition that
negatively affects a patient’s quality of life. It
occurs mostly in women and the estimated ratio of
women to men is 9:1(14).
The exact etiology of BPS/IC is still controversial and various pathophysiology theories have
been proposed. The most recent one is based on a
disruption in the GAGs layer of the bladder
mucosa. This results in the loss of the normal permeability barrier and allows transfer of substances
from urine to the bladder interstitium, which finally
causes a cascade of reactions and disease progression(2).
1180
Diagnosis of BPS/IC is based on symptoms
and exclusion of other painful bladder conditions
that resemble BPS/IC but have a different identifiable cause. A variety of tools are available to help
eliminating all other possibilities and identify
BPS/IC(15). Beside laboratory and radiological evaluations we used cystoscopy with hydrodistention,
bladder biopsy, urodynamic testig, voiding diaries
and symptom surveys in order to exclude confusable diseases.
Although cystoscopy with hydrodistantion is
no longer considered mandatory for the diagnosis
of BPS/IC, cystoscopic findings can be helpful to
rule out bladder cancer, stones or foreign bodies as
causes of urinary urgency and frequency symptoms(16-18). It also allows photodocumentation of the
bladder inflammation (glomerulations, submucosal
hemorrhages, ulcers), determination of the bladder
capacity under anesthesia and definition of the
degree and type of microscopic inflammation if
biopsies are performed(19). Furthermore, in a study it
has been shown that approximately half of patients
experience short-term therapeutic benefit following
hydrodistention(18). But still there are controversies
about the therapeutic affect of bladder hydrodistantion Hanno et al. showed that BH provides symptoms relief at 6 months only in 0-7% of treated
patients(20). After hydrodistantion Hunner’s lesion
and glomerulations can be seen. Today it has been
shown that glomerulations are not specific for
BPS/IC and they can be seen in defunctionalized
bladders, after intravesical chemotherapy and in up
to 40% of normal women undergoing tubal ligation(20-22).
All of the patients in our study underwent cystoscopy with hydrodistantion in order to exclude
confusable diseases and none of them had Hunner
lesions or other confusable diseases but all patients
had submucosal ectasias in at least three bladder
quadrants.
Bladder biopsy is not essential for the diagnosis of IC and is often not indicated(23). Biopsy can be
used to rule out other diseases, especially carcinoma in situ. Although there are no pathognomonic
histological features for BPS/IC, biopsy findings
can establish the degree of chronic inflammation,
the presence of inflammatory cells and the presence
of vasodilatation in the mucosal layers(4,24).
In our case series, biopsy samples were
obtained from 9 patients who had suspicious areas
during cystoscopy. “Partial desquamation of the
superficial epithelium, chronic active cystitis,
Fetullah Gevher, Mustafa Bilal Tuna et Al
mononuclear cellular infiltration” were found in 6
of them. Three patients had no specific pathologic
abnormalities.
Urodynamic testing is not required for a diagnosis of BPS/IC, but it may help eliminate other
bladder disorders such as detrusor instability, stress
urinary incontinence and bladder outlet obstruction (16,24,25) . The Interstitial Cystitis Data Base
(ICDB) study reported involuntary bladder contractions in 14.6% of IC patients(26). In our study 16
patients underwent urodynamic testing study and 3
(18.7%) patients had involuntary bladder contractions.
Symptom surveys and voiding diaries are very
usefull in screening for BPS/IC and in the followup evaluation of patients with BPS/IC(16,24). ICSI,
PUFSS and ICPI are the most commonly used
symptom surveys(14,15). Both surveys ask the patient
about urinary urgency, frequency, nocturia and pain
aand the impact of these symptoms on daily life.
The PUFSS evaluates sexual dysfunction as well.
The PUFSS, ICSI, ICPI are simple to administer
and may clarify symptoms that the patient failed to
explain during history taking(27). We also used voiding diaries, PUFSS and ICSI in order to understand
and standardise the symptoms and to evaluate the
outcomes of the treatment.
Many different kinds of therapies have been
proposed for the treatment of BPS/IC. Intravesical
therapy options such as HA, heparin sulfate and
chondroitin sulfate aims to restore the GAG layer
and to reduce inflammation, mast cell activation
and in addition repair the damaged urothelial lining.
HA is an important component of GAG layer.
It is reported that instillation of HA provides longterm improvement for patients with BPS/IC(28). HA
is not only a regenerating factor for the defected
GAG layer but it is also able to attach to several
cellular receptors that are overexpressed in inflammatory conditions and by this way can inhibit
release of pro-inflammatory molecules from mast
cells and alleviate the inflammatory process(29).
Some trials proved the efficacy of HA in the
treatment of BPS/IC. Leppilahti and colleagues
administered four weekly intravesical instillations
of 40mg HA after BH in 11 patients and observed a
decrease in urinary frequency (less than 75%) and
in a visual analogue scale (VAS) pain score (less
than 26%)(29).
Morales reported a 71% response to the treatment with HA after 12 weeks(30). In an another study
the long-term efficacy of intravesical HA therapy
Effect of intravesical hyaluronic acid treatment on bladder pain syndrome/interstitial cystitis
was proved. 68.6% of patients responded after a
mean follow-up of 4.9 years, 50% reported complete remission without any additional therapy and
41.7 % patients with recurrences were improved
with HA maintenance therapy(31). Kallestrup at al
reported a 65% of positive response rate after four
weekly plus two monthly bladder instillations of
40mg HA in 20 patients with BPS/IC(32).
Cervigni and colleagues showed a statistically
significant improvement in ICSI/ICPI and PUFSS
and VAS score after 20 weekly and 3 monthly
intravesical instillations of 40mg HA and CS over 8
months of follow up, with no cases of complications after intravesical instillation of HA and CS in
a group of 23 patients(33). Similar reults were reported by Porru and colleagues, 6 months after treating
20 patients with a combination of HA and CS(34).
Our study was based on a protocol using ICSI/
ICPI and PUFSS questionnaires. There were statistically significant reductions in pre and post treatment ICSI/ICPI and PUFSS scores. There was also
a significant increase in urine volume per void, and
decrease in frequency of daily voiding. In addition,
intravesical combination therapy with HA was well
tolerated and there were no adverse affects.
Although this study was a prospective study,
still it has some limitations which are mainly represented by the small sample size, the short follow up
and the lack of a placebo control group. However,
the encouraging results of this study will give countenance to researchers on making future multicentral, randomized and controlled studies on a larger
population.
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Conclusions
Despite the limitations of this study, our findings verifies that the role of intravesical treatment
with HA is a safe and effective option for the treatment of BPS/IC. It produced improvement in symptoms and there were no known side effects.
Nevertheless, further randomized controlled studies
with a larger number of patients and a longer follow-up period are needed to confirm these encouraging results and to optimize the treatment protocol
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Abbreviations
HA: Hyaluronic acid
BPS/IC: Interstitial Cystitis/Bladder Pain Syndrome
ICSI: The O'Leary-Sant Interstitial Cystitis Symptom Index
ICPI: Problem Index Scale
PUFSS: Pelvic Pain and Urgency/Frequency Patient Symptom
Scale
GAG: Glycosaminoglycans
VAS: Visual Analogue Scale
_________
Correspnding author
ÖNDER KARA M.D.
Hacettepe University, School Of Medicine, Urology
Ankara
(Turkey)