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to the bladder, pain may radiate to the vulva, clitoris, vagina, rectum, perineum, or
sacrum and is relieved by voiding. Patients often report numerous pain sites outside
the bladder/pelvic region. Visual analog scale (VAS) is a useful tool to grade pain.
Cognitive, behavioral, emotional, and sexual consequences of the pain syndrome
must also be evaluated. Other pain syndromes associated with BPS/IC such as irri-
table bowel syndrome, bromyalgia, and chronic fatigue syndrome should be inves-
tigated. Increased numbers of body pain sites are associated with poorer patient
outcomes [32]. A general medical history should give special emphasis to previous
pelvic operations or radiation treatment, urinary tract infections, and autoimmune or
other urologic diseases.
BPS/IC patients usually complain of frequency and nocturia. A 3-day voiding
diary with volume intake and output is typically used to assess urinary frequency
and maximum functional bladder capacity.
Two questionnaires have been used to assess symptoms and problems of these
patients: O’Leary-Sant (OLS) and Pain and Urgency/Frequency (PUF). These ques-
tionnaires address urgency, frequency, nocturia, pain, as well as the bothersomeness
for those symptoms [33]. The OLS symptom and problem score has been recog-
nized as the most reliable and valid instrument [12]. These questionnaires can be
supplemented with the assessment of the quality of life.
Physical examination should be performed, including the lower abdomen for
bladder tenderness and mapping pain during inspection. Special attention should be
given to the presence of kyphosis, scars, hernia, abduction/adduction of the hips,
and hyperesthetic areas.
Bacterial cultures for Chlamydia trachomatis, Ureaplasma urealyticum,
Mycoplasma hominis, Mycoplasma genitalium, Corynebacterium urealyticum,
Candida species, and Mycobacterium tuberculosis should be performed.
BPS/IC patients usually disallow cystoscopy at outpatient clinic. However, cys-
toscopy with hydrodistension under anesthesia should be carried out to exclude
other identiable causes. Nevertheless, there is no consensus about when it should
be performed, immediately at diagnosis [
2] or later if patients are refractory to stan-
dard management [34]. Bladder signs of BPS/IC are glomerulations and Hunner’s
lesions. Glomerulations are described as punctate/petechial hemorrhages after
hydrodistension. Hunner’s lesions are most often recognized on the lateral walls
using bladder distension. Before hydrodistension resemble a circumscript inam-
matory reaction with radiating small vessels and central scar with brin deposit.
After distension, Hunner’s lesions look like a mucosal rupture with waterfall-like
bleeding [12]. Hydrodistension under anesthesia also gives important information
about potential functional capacity [12].
Bladder biopsies can be performed during cystoscopy under anesthesia. They are
helpful to characterize histologically each BPS/IC patient and to exclude confusable
diseases, for example, carcinoma in situ. Common ndings include epithelial denu-
dation, submucosal inammation, granulation tissue, and hemorrhage. More spe-
cic ndings such as mast cell inltration and bladder wall brosis might also give
information about disease severity and prognosis [35]. Up to 50% of BPS/IC
patients have normal biopsies [12].
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ESSIC, in an attempt to clarify this disease, proposed a classication based on
ndings during cystoscopy with hydrodistension (presence of Hunner’s lesions/glo-
merulations) and morphological ndings in bladder biopsies (presence of inam-
matory inltrates and/or detrusor mastocytosis and/or granulation tissue and/or
intrafascicular brosis).
Imaging with ultrasound or computed tomography and urodynamics are rarely
necessary in BPS/IC.
Potassium sensitivity test or Parson’s test consists on instilling a 0.4Mol solution
of potassium chloride (KCL) into the bladder [36]. This test is no longer recom-
mended because of the long-lasting pain persisting after the procedure and its posi-
tivity in both healthy and idiopathic overactive bladder patients at this concentration.
This test also does not give any information regarding efcacy of treatment and
outcome [37].
7.5 Bladder Pain Syndrome/Interstitial Cystitis
Management
There is no cure for BPS/IC. Thus the main goal of available treatments is to
decrease the intensity of lower urinary tract symptoms, in particular pain. There is a
50% incidence of temporary remission unrelated to therapy, with a mean duration
of 8months. Therefore, a step-by-step approach is recommended (Fig.7.1).
Stress reduction, exercise, warm tub baths, and efforts by the BPS/IC patient to
maintain a normal lifestyle all contribute to improving overall quality of life.
Biofeedback, soft tissue massage, acupuncture, and other physical therapies may
aid in muscle relaxation of the pelvic oor [38].
Many patients nd that their symptoms are adversely affected by specic diets.
Nevertheless, diets should be introduced on an individual basis. Triggering food
may include caffeine, alcohol, articial sweeteners, hot pepper, and beverages like
cranberry juice that might acidify the urine.
Long-term use of analgesic medications represents a fundamental part of the
treatment of a chronic pain condition like BPS/IC.Concerning more specic ori-
ented therapies, few of the oral drugs commonly used have been supported by
unequivocal evidence of efcacy in large, multicenter, randomized controlled clini-
cal trials (RCTs). There is little or no evidence that any therapy changes the natural
history of the disease. Pentosan polysulfate sodium (PPS) is a heparin-like macro-
molecule that resembles urothelium GAG and remains the only oral therapy
approved by the Food and Drug Administration (FDA). PPS is postulated to act by
replacement of the GAG layer as well as by inhibition of mast cell degranulation
[39]. However, PPS showed efcacy in 30% of BPS/IC patients after 6months of
medication in its rst study [40]. Amitriptyline, a tricyclic antidepressant, has anti-
cholinergic and sedative properties by decreasing 5-hydroxytryptamine reuptake. It
stabilizes mast cells and blocks the actions of histamine [41]. Nevertheless, all
RCTs conducted with amitriptyline were negative. Only the subanalysis of the RCT
conducted by the Interstitial Cystitis Collaborative Research Network (ICCRN) for
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doses above 50mg/day showed efcacy, however with increased risk of side effects
[41]. Hydroxyzine is a H1-receptor antagonist that inhibits mast cells by blocking
serotonin release in the bladder. At dosages of 25–50mg daily, it was suggested to
decrease the severity of the symptoms in 40% of patients. In patients that had per-
sonal history of allergies, the success rate reached 55% [42]. Again, all RCTs con-
ducted with hydroxyzine were negative [43]. Tanezumab is a humanized anti-NGF
monoclonal antibody that binds with high afnity and specicity to NGF, prevent-
ing it from interacting with receptors on nociceptive neurons. Tanezumab was
investigated for the treatment of BPS/IC pain in a phase 2 RCT against placebo. The
modest efcacy (only 50% of patients having a 30% or greater reduction of pain
score) and the serious adverse events do not suggest tanezumab as a promising treat-
ment for BPS/IC [44]. Other drugs being tested for BPS/IC include micro-RNA
manipulation, APF antagonists, selective cannabinoid type-1 receptor agonists, and
phosphodiesterase type 5 inhibitors. APF antagonists revert tight junction damage
in laboratory models [45]. Micro-RNA manipulation may mediate downregulation
of NK-1 receptor in BPS/IC [46]. Selective cannabinoid type-1 receptor agonists
Further treatment options selected based on:
Symptom phenotype
Degree of quality of life impairment
Patient preference
Availability/access
Adverse event profile
SYMPTOM PHENOTYPES (adopted from Nickel et al. 2014
216
)
IC/BPS
All patients:
1. Patient education
2. Dietary modifications
3. Sexual counselling
Urinary*
Bladder training
Anticholinergics
Intravesical
agents (Heparin,
DMSO, HA, CS,
PPS, oxybutynin)
Hydrodistension
Botulinum toxin A
Sacral neuromodulation
Radical surgery
Psychosocial
Stress management
and
psychological support
Non-Hunner’s Hunner’s
Infectious Neurologic/systemic Tenderness
Antimicrobials Gabapentanoids
Hydroxyzine
Cimetidine
Sacral neuromodulation
Pelvic floor
physiotherapy,
massage,
acupuncture,
trigger point,
injections
Organ-specific*
Amitriptyline
Cimetidine
Hydroxyzine
PPS
Quercetin
Intravesical agents
(DMSO, Hep, HA,
CS, alkalinized
lidocaine, PPS)
Hydrodistension
Botulinum Toxin A
Radical surgery
CyA
Endoscopic
(Fulguration,
laser, resection,
steroid injection)
Novel therapies
(hyperbaric oxygen)
Radical surgery
* Almost all patients will have these phenotypes.
Fig. 7.1 Recently proposed management paradigm for the treatment of IC/BPS according to the
Canadian Urological Association
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signicantly decrease inammatory activity in the urothelium [47]. Daily low-dose
sildenal also proved to be an easy, well-tolerated, and effective treatment [48].
Intravesical therapy is another important treatment option. It opens the possi-
bility to directly apply higher drug doses or even to deliver substances that orally
are impossible to use. Dimethyl sulfoxide (DMSO) is the only intravesical ther-
apy approved by the FDA for BPS/IC.DMSO is an organic solvent, a by-product
of the paper pulp industry, which has analgesic and anti-inammatory properties,
muscle relaxant, and collagen-dissolution effects [49]. DMSO alone currently
holds an evidence grade C recommendation for BPS/IC, which can be explained
by the inexistence of any positive RCT [12]. Moreover, BPS/IC patients fre-
quently feel a typical garlic body odor, when they receive more than 50mL of
50% DMSO per week. DMSO is often combined in intravesical cocktail solutions
(lidocaine, heparin, and/or sodium bicarbonate) that are administered weekly or
biweekly. There is no study to conclusively show that these preparations are any
more effective than DMSO alone [50]. Intravesical lidocaine or its alkalinized
form has shown value in the management of pain and urgency in BPS/IC [51].
Alkalinized lidocaine had a signicantly immediate effect on mean pain score,
which lasted for 8days after the instillation [52]. Another molecule that can be
instilled is PPS.Through this route it can achieve higher concentrations near uro-
thelium than when given orally. In a recent RCT, simultaneous oral and intravesi-
cal PPS showed signicant advantage of use over placebo or oral PPS alone [53].
GAG layer restitution has also been attempted with chondroitin sulfate and hyal-
uronic acid. Nevertheless, RCTs against placebo of intravesical sodium chondroi-
tin sulfate or hyaluronic acid were negative or showed high recurrence rate during
the rst year [54]. Sensory type C bers are responsible for pain transmission in
BPS/IC.Thus, desensitizing TRPV1 receptor and inactivating C bers can be an
alternative approach. Several studies showed a benecial effect of resiniferatoxin
(RTX) applied intravesically [42]. Nevertheless, the only large RCT conducted
with RTX against placebo was negative [55]. Other RCT examined the effect of
the intravesical instillation of bacillus Calmette-Guérin (BCG) and concluded that
it has no clinical effect on BPS/IC [
56].
Hydrodistension under anesthesia in addition to being a diagnostic tool can be
also used as a treatment for BPS/IC.After the initial cystoscopic examination, the
physician “hydrodistend” the bladder by lling it with uid at low pressure (60–
80 cm) and keeping it full for 1–5 min before letting the uid out. Long-term
symptom- free periods may follow the procedure. Exactly why this procedure has
therapeutic benets for some patients is still unknown. A recently conducted study
examined patients with BPS/IC who were treated with hydrodistension and subse-
quent bladder training. Of the 361 patients recruited into this uncontrolled study,
only 13.4% described urgency symptoms 8weeks after hydrodistension, and more
than 80% of patients showed improvement in their BPS/IC ares of pain associated
with menstruation and sexual intercourse [57]. Nevertheless, long-term results are
not so encouraging [12].
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Surgical fulguration of Hunner’s lesions with LASER/resection was shown to be
effective in relieving symptoms for up to 12months or more in BPS/IC patients [58].
The drawback of this option is that it is only effective in the subset of ulcerated patients.
Neuromodulation is a procedure in which the S3 sacral nerve or the pudendal
nerve roots are stimulated by a mild electrical current. Several studies have shown
its safety and efcacy in the management of refractory BPS/IC, with good long-
term results [59]. Nevertheless, it is an expensive treatment with frequently reported
side effects, namely, bleeding, infection, program malfunction, or lead displace-
ment [59]. Posterior tibial nerve stimulation is designed to deliver stimulation to the
sacral nerve via the posterior tibial nerve at the medial malleolus, being less invasive
than neuromodulation. However, its efcacy in BPS/IC was never proved [60].
A relatively new technique for refractory BPS/IC patients is the use of hyper-
baric oxygen therapy. It has been shown that there is increased expression of HIF
1α
and VEGF in patients with BPS/IC, supporting the use of hyperbaric oxygen ther-
apy for the treatment of BPS/IC [61]. This treatment allows hyperoxia of the urothe-
lium, resulting in leucocyte activation and promotion of healthy granulation tissue
growth. However, there is no RCT supporting this procedure in BPS/IC.
Pain relief remains very difcult to achieve with standard treatment, leading sev-
eral investigators to use onabotulinum toxin A (OnaBotA). The toxin impairs noci-
ceptive bers by preventing neurotransmitter release [62]. Intravesical OnaBotA
administration also decreases urinary NGF [63] and VEGF [64], two important
molecules in the pathophysiology of BPS/IC. Altogether, these facts indicate a
strong antinociceptive effect of OnaBotA in the bladder. Since 2008, some authors
showed that 100 U OnaBotA improve symptoms in refractory BPS/IC patients,
independently of their initial ESSIC classication or phenotype [65–68]. Two major
questions around intravesical OnaBotA are the controversy around which should be
the best local of administration and which should be the ideal dose. In a recent ran-
domized placebo-controlled trial, intra-trigonal injections of 100 U signicantly
improved bladder symptoms and quality of life [69].
Urinary diversion with bladder conservation, supratrigonal cystectomy with
enterocystoplasty, subtrigonal cystectomy, or radical cystectomy including excision
of the urethra with urinary diversion should be the last resort. Refractory patients
with Hunner’s lesions and smaller bladder capacities under anesthesia are probably
the candidates [70]. Unfortunately, urinary diversion or cystectomy cannot guaran-
tee a pain-free result [71].
7.6 Bladder Pain Syndrome/Interstitial Cystitis Conclusions
Nowadays, the traditional structured monotherapy approach should not be consid-
ered the best standard of care for BPS/IC patients (Fig.7.2). A tailor-made treat-
ment plan directed toward the patient’s unique clinical phenotype will ultimately
lead to a better outcome.
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R. Almeida Pinto
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© Springer Nature Switzerland AG 2019
F. R. Pérez-López (ed.), Postmenopausal Diseases and Disorders,
https://doi.org/10.1007/978-3-030-13936-0_8
V. K. Tailor · G. A. Digesu (*)
Department of Urogynaecology, Imperial College NHS Trust, London, UK
e-mail: vishatailor@nhs.net; a.digesu@imperial.ac.uk
8
Overactive Bladder
VishaK.Tailor andG.AlessandroDigesu
8.1 Introduction
Overactive bladder (OAB) has been dened by the International Continence Society
(ICS)/International Urogynecological Association (IUGA) as urinary urgency with
or without urge urinary incontinence, usually accompanied by frequency and noctu-
ria in the absence of a urinary tract infection or other pathology [1]. The symptoms
can be distressing affecting all aspects of a woman’s quality of life (QoL) including
social, work-related, emotional and sexual function [2].
OAB has a reported overall prevalence of 16.9% in women which increases with
age. Women under 25 have a prevalence of 4.8% increasing to 30.9% in women
over 65 [3]. Prevalence has separately been reported as high as 38% in postmeno-
pausal women [4].
8.2 Pathogenesis
OAB is a symptom-based diagnosis with an aetiology that is still poorly understood.
It can be associated with detrusor overactivity which is diagnosed by urodynamic
studies. Spontaneous or provoked involuntary contractions of the detrusor muscle
during the lling stage of micturition can be observed.
OAB is more prevalent in postmenopausal women with symptoms of genitouri-
nary syndrome of menopause (GSM). Symptoms include vaginal dryness, burning,
dyspareunia and urinary tract infections. The aetiology can be linked with genito-
urinary atrophy which can be attributed to oestrogen deciency during the meno-
pause with reduced oestrogen receptors in tissues such as vaginal epithelium and
the bladder trigone [5]. This is also thought to contribute to urinary symptoms
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