Disease type
Confusable diseases
Bladder diseases
Overactive bladder
Neurogenic bladder
Radiation cystitis
Bladder calculus
Bladder cancer
Prostate and urethral diseases
Benign prostatic hypertrophy
Prostate cancer
Urethral stenosis
Urethral diverticulum
Genitourinary infections
Bacterial cystitis
Urethritis
Prostatitis
Gynecologic diseases
Endometriosis
Uterine myoma
Vaginitis
Postmenopausal syndrome
Other conditions
Polyuria
Overactive pelvic floor
A retrospective analysis from the IC Database (ICDB) pointed out the most common baseline pain site was lower abdominal (80 %), urethral (74 %), and low back (65 %), with the majority of patients describing their pain as intermittent [53].
Questionnaires can be helpful in screening for BPS/IC. The most commonly used screening tools are the Pelvic Pain, Urgency, Frequency symptom scale (PUF) and the O’Leary–Sant Symptom and Problem Index [54, 55]. Both surveys include questions regarding pain, urgency, frequency, and nocturia and how these symptoms affect quality of life.
Physical examination is a critical component of diagnosing BPS/IC. Since the bladder is the pain generator, tenderness with single-digit examination of the trigonal area can help establish a diagnosis of BPS/IC [56]. Pelvic floor tenderness upon palpation of the levator muscles is a common finding [57]. Physical examination should also address high tone of the pelvic floor muscles, and hypersensitivity of the perineal area, using the Kaufman Q-tip touch sensitivity test that might screen for the presence of vulvar vestibulodynia (VVS) [58].
As regards ancillary testing , urine analysis should be carried out to rule out hematuria, urine culture is required to identify bladder infection and cytology can help rule out bladder cancer. Several additional optional diagnostic tests are used but diagnostic evaluation varies among urologists/urogynecologists, in different centers [59–61] and among the USA, Europe, and Asia (Table 5.1) [16, 62].
Urodynamic studies can highlight detrusor overactivity or reduced bladder capacity without detrusor overactivity (bladder hypersensitivity), suggestive of BPS/IC [63–65]. Mild impairment of the voiding phase with detrusor-sphincter discoordination is probably related to the dysfunctional pelvic floor behavior.
Local cystoscopy is not mandatory but is a good preliminary investigation to rule out other conditions (e.g., bladder stone, hematuria, or cancer). Diagnostic cystoscopy can identify Hunner’s ulcer [66], the typical bladder lesion seen in BPS/IC. Typically, the ulcer is recognized as a well-demarcated reddish mucosal lesion lacking normal capillary structure. In addition, some scars or fissures with a rich hypervascularization or a pale mucosal appearance may be present, as an indirect index of hypovascularization.
Cystoscopy with hydrodistention under anesthesia has been proposed by the NIDDK research criteria, but is now considered too restrictive [61]; however, it remains the most common diagnostic procedure performed in patients with BPS/IC, especially in Europe [67]. Hydrodistention is carried out using different methodologies, making comparison between studies difficult [58, 62, 68]. It is useful to exclude other pathologies, to identify the presence of “classic” BPS/IC with “Hunner’s lesions” and document urothelial bleeding (glomerulations), even though these have also been noted in the bladders of normal women undergoing tubal ligation [69].
Bladder biopsy should be carried out once the hydrodistention has been completed, to avoid the risk of bladder rupture. Biopsies can show the presence of mast cell infiltration, and orientate specific therapy choices. Biopsy with histopathology may be necessary to exclude neoplasm and eosinophilic or tuberculotic cystitis. The European Society recommends a count of tryptase-positive bladder mast cells with >28 mast cells/mm to be defined as detrusor mastocytosis and considered diagnostic for BPS/IC [61, 62, 70]. An increased number of mast cells has also been recently proposed as a diagnostic criterion for provoked vestibulodynia [71].
There are no recognized blood or urine markers diagnostic of BPS/IC. Recently APF, a substance identified as a frizzled-8 surface sialoglycopeptide [72], has been found to be increased in the urine of BPS/IC patients. APF is detected by its ability to decrease in vitro proliferation of bladder epithelial cells and its activity was enhanced in BPS/IC but not in other urologic disorders [73]. Urine APF levels also seems to discriminate between BPS/IC and CPPS in men [74]. However, APF still needs to be validated and results of its investigation need to be reproduced by further research.
Classic BPS/IC might be differentiated from non-ulcerating disease by its elevated urine nitric oxide (NO) levels [75].
Other urinary markers include heparin-binding epidermal growth factor-like growth factor (HB-EGF), histamine, methylhistamine, and interleukin-6 (IL-6) [76, 77]. Four proteins that differed significantly between BPS/IC and controls have been identified, with uromodulin and two kininogens found to be higher for controls and inter-alpha-trypsin inhibitor heavy chain H4 higher for BPS/IC [78]. Urinary concentration of neutrophil elastase is increased in patients with pain and a small bladder capacity [79]. These markers are not necessarily precise predictors of ulcers and/or symptom severity [80].
Intravesical administration of 40 mL of a solution of 40 mEq of potassium chloride in 100 mL of water (potassium sensitivity test—PST), with pain and urgency scored by the patient as compared to administration of sterile water has been proposed for BPS/IC diagnosis [54]. However, this test’s sensitivity and specificity is only about 75 % and the participants at the International IC Consultation in Rome recommended that it should not be used for diagnostic purposes because of its low prognostic value [81].
5.6 BPS/IC and Overactive Pelvic Floor
Many patients with Bladder Painful Syndrome/Interstitial Cystitis (BPS/IC) have concomitant PFD, with muscle tenderness and spasm also known as Overactive Pelvic Floor (OPF).
Several studies found that myofascial pain and OPF are present in as many as 85 % of patients with BPS/IC and/or Chronic Pelvic Pain (CPP) Syndrome [82]. The mechanism is likely very similar to Category IIIB Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CCPS) in the male population. PFD exacerbates BPS/IC symptoms and has been reported to appear in response to events such as bladder inflammation, gait disturbance, and trauma [83, 84].
5.6.1 Pelvic Floor Disorders
PFDs have been classified as hypotonic, or low tone pelvic floor dysfunction (LD), typically associated with urinary and/or fecal incontinence and/or pelvic organ prolapse (POP), or hypertonic dysfunction (HD), which is often associated with Overactive Bladder (OAB), Chronic Pelvic Pain Syndrome (CPPS), BPS/IC, and sexual pain disorders. These dysfunctions are generated by an antidromic reflex that is estimated to be present in 70 % of women [85–87]. In the colorectal literature it is defined also as tension myalgia and levator ani syndrome [88, 89] and can contribute to symptoms of urinary frequency, urgency, dysuria, urinary and fecal retention, dyspareunia, and/or vaginismus [12, 86, 87].
5.7 Pathophysiology
In a normal bladder peripheral neural transmission is mediated by A-fibers which are myelinated, high speed transmission nerves transferring tension, pain, and cold. Unmyelinated C-fibers are low speed transmission neurons in charge of burning, painful and itching stimuli. C-fibers are normally silent and become activated in response to bladder inflammation or irritation. Inflammation, pain, or of pelvic visceral trauma may transfer noxious stimuli to the sacral cord, which can result in pelvic floor muscle dysfunction due to sacral nerve hypersensitivity and initiate a sacral cord wind-up effect [93–97].
The “Guarding Reflex ” is a viscero-muscular reflex activated with the aim to increase the tone of the pelvic floor during routine daytime activity [98]. The afferent autonomic bombardment occurring in BPS/IC patients may enhance and maintain such guarding reflex, resulting in pelvic floor overactivity.
5.8 Symptoms
Even though there are symptomatological similarities between BPS/IC and PFD, there are also some differences related to the pelvic floor non-relaxing behavior. Pain symptoms are often vague and poorly localized. Pain is described as achy and throbbing, and is often accompanied by feelings of pressure or heaviness. This feeling is often similar to that described by patients with POP, yet on examination no significant prolapse is observed [92]. Pain often worsens as the day progresses and is typically exacerbated by pelvic floor muscle activities like sexual intercourse or voiding. Factors such as job stress, constipation, or menses may trigger myofascial pain.
Patients with a significant myofascial pain component will often report leg or groin pain occurring with bladder filling and increased urinary frequency during the daytime, in the absence of nocturia. The pressure arising from pelvic floor overactivity may be perceived as a need to void. As the pelvic floor relaxes during sleep, the need to void is generated only by bladder volume and not by pelvic floor pressure. As documented by several authors [99, 100], in patients with BPS/IC pelvic floor physiotherapy combined with bladder-directed therapy is more effective than the latter alone.
5.9 Physical Examination
Clinical evaluation of the pelvic floor begins with observation of pelvic floor muscle activity during the process of actively contracting and relaxation. Mere observation of the perineum and introital area in the dorsal lithotomy position during the performance of an active pelvic floor muscle contraction is often quite revealing. Patients with HPFD are unable to increase contractile strength and therefore cannot produce an effective contraction. Spontaneous muscle fasciculation can often be observed due to muscle fatigue. A lubricated cotton tip applicator is then gently used to evaluate for signs of allodynia and vulvodynia.
At this point the examiner should place a generously lubricated single finger in the vagina to assess pelvic floor awareness and the ability to contract and relax the levator ani. Many scales are available to document strength, tone, and tenderness of any vaginal compartment (Oxford scale -49-50/1). Often patients with HPFD will have a “V” configuration and as a finger is advanced it will drop off the shelf caused by the contracted levator muscles and drop down onto the coccygeus muscle. Active trigger points are often identified as exquisitely tender areas palpable as a small 3–6 mm nodule within a taut band that reproduces the patient’s pain, as well as the referral pattern of her pain. Tenderness upon palpation of each ischial spine and underneath the pubic rami should be assessed.
5.10 Ancillary Testing
5.10.1 Electromyography
The best objective tool clinically available for the assessment of pelvic floor overactivity is surface EMG. As discussed in Chap. 12 of this text, reliability and validity of this measure continues to present a challenge. The following findings will be suggestive of pelvic floor overactivity:
1.
Elevated and unstable resting baseline activity
2.
Poor recovery
3.
Poor post-contraction and relaxation
5.10.2 Urodynamic Testing
Typical urodynamic findings include fluctuating or interrupted flow, abnormal voiding phase pressure-flow studies, elevated urethral pressure at rest and urethral instability. Schmidt and Vapnek performed urodynamics in patients with IC or severe urgency and frequency and observed that pain episodes paralleled behavioral changes in the sphincter more than in the bladder [103]. A complete discussion of urodynamic testing is available in Chap. 14.
5.10.3 Defecography
When symptoms involve obstructed defecation and rectal pain, defecography can be used to identify the presence of a nonrelaxing pelvic floor or paradoxical activity of the pelvic floor during defecation.
5.11 Myofascial Pain Syndrome
Myofascial pain is present in 12–87 % of pelvic pain patients. Myofascial pain disorder can be primary or secondary. The latter is associated with another pain disease such as BPS/IC, Vulvodynia, or IBS. If this is the case, the primary pain generator must be treated as well as the myofascial component.
5.12 Treatment Strategies
5.12.1 Bladder Pain Syndromes/Interstitial Cystitis
There is no curative therapy for BPS/IC. This is consistent with the fact that the causes of BPS/IC are yet not understood and the pathophysiology remains unclear. Therefore, the therapeutic strategy is to alleviate symptoms, thereby interfering with the potential disease mechanisms and improving quality of life.
Because BPS/IC is a chronic disease, realistic expectation of treatment should be discussed with patients. Remission may be attained but should not be expected, and even when it is attainable, months of medical treatment may be required.
Periods of remission commonly alternate with exacerbations and patients need to be encouraged that therapy is not failing.
5.12.2 Conservative Therapy
Behavioral modification may have modest benefit for IC patients (grade of recommendation B). Barbalias et al. evaluated a bladder training technique as an adjunct to intravesical oxybutynin in patients with IC; there was a modest improvement in O’Leary–Sant questionnaire at 6 months [104]. Chaiken et al. reported similar results with diary-timed voiding and pelvic floor muscle training [105]. There are no randomized controlled trials (RCTs) attesting the efficacy of pelvic floor physical therapy. Biofeedback and soft tissue massage may aid in muscle relaxation of the pelvic floor [105].
Manual physical therapy to pelvic floor myofascial trigger points twice per week for 8–12 weeks also resulted in moderate to marked improvement in 7/10 BPS/IC patients.
Modified Thiele intravaginal massage of high-tone pelvic floor muscle trigger points twice per week for 5 weeks has been shown to improve the O’Leary–Sant Index (grade of recommendation C). A discussion of physical therapy treatment of OPF is available in Chaps. 16, 17, and 18.
Commonsense dietary changes, especially avoidance of potential bladder irritancy as identified by individual patients may be beneficial (grade of recommendation B). A majority of BPS/IC patients seem to have symptom exacerbation related to the intake of specific foods and beverages: coffee, spicy foods, and alcoholic beverages.
However, different patients seem to be affected to different degrees by specific foods and beverages and patients should avoid only those that they find worsen their symptoms.
5.12.3 Medical Therapy
Medical therapies for BPS/IC include oral, subcutaneous, and intravesical agents. These drugs are categorized according to their intended point of action within the disease process.
5.12.3.1 Protection of the Mucosal Surface
One of the theories in the pathogenesis of IC is that deficiency of the GAG layer causes symptoms related to increased permeability of the urothelium . A number of agents have been used to improve the integrity of the mucosal surface.
Pentosan polysulfate (PPS ), a branched polysaccharide presumably acting to “replenish” the GAG layer, is the only oral drug approved in the USA for BPS/IC (grade of recommendation B, level of evidence 2). One study of PPS (300 mg/day) used for 3 years showed it was twice as potent as placebo (18 %) in reducing pain but the placebo response was unusually low [1, 83]. A randomized double-blind multicenter study evaluated PPS with a range of doses (300, 600, or 900 mg per day) in 380 BPS/IC patients with >6 months’ symptoms and positive cystoscopic examination but no placebo control. With a follow-up of 32 months, they reported a 45–50 % response rate (50 % or greater improvement on the Patients’ Overall Rating of Symptoms Index—PORIS), irrespective of dosage [106]. In a recent prospective study, 41 patients with BPS/IC were divided into three groups according to their response to PPS (major, intermediate, minor). They were administered subcutaneous heparin 5000 IU t.i.d. for 2 days, followed by 5000 IU b.i.d. for 12 days plus 300 mg PPS per day, compared to 17 nonmatched patients taking PPS alone. Thirty-two percent of the patients in the minor response group reported a significant improvement in “overall well-being” over that of PPS alone [107].
Hydroxyzine is a histamine-1 receptor antagonist, with additional anxiolytic, sedative, anticholinergic, and mast cell inhibitory properties, which has been shown to reduce neurogenic bladder inflammation [108] (grade of recommendation D, level of evidence 1). Studies on hydroxyzine in treating BPS/IC symptoms report mixed results. One open-label study showed a 55 % reduction in symptoms, particularly in patients who suffered from allergies [109].
Cimetidine is a histamine-2 receptor antagonist (grade of recommendation D, level of evidence 4). It has been reported to decrease median symptom score in 34 BPS/IC patients, but no apparent histological changes in the bladder mucosa were observed [110].
l-Arginine is a natural substrate of nitric oxide synthase (NOS) (grade of recommendation D). It may reactivate NOS activity, which is suppressed in IC, and relieve symptoms. No significant effect was observed in double-blind studies [111].
5.12.3.2 Intravesical Instillation and Bladder Wall Injections
Intravesical and subcutaneous heparin has been used for the treatment of IC since the early 1960s. With intravesical instillation , heparin does not have systemic anticoagulant effects. In one study on 48 patients with IC self-administered intravesical heparin (10,000 IU in 10 mL sterile water three times weekly for 3 months), 56 % of patients attained clinical remission after 3 months [112].
Intravesical dimethylsulfoxide (DMSO) remains the basis of intravesical therapy for IC (grade of recommendation B, level of evidence 2). It has been shown to reduce symptoms for up to 3 months. Its mode of action includes anti-inflammatory and analgesic effects, muscle relaxation, mast cell inhibition, and collagen dissolution. Patients treated with DMSO have reported a 50–70 % reduction of symptoms, although the relapse rate can be up to 35–40 % [113]. Administration in combination with various other agents including hydrocortisone, heparin, and sodium bicarbonate has been reported to improve response [114].
Intravesical hyaluronic acid (grade of recommendation C, level of evidence 4) has been used with long-lasting moderate efficacy and no side effects, but a recent multicenter study found no significant efficacy (Interstitial Cystitis Association—Physician perspectives, unpublished data).
Chondroitin sulfate (grade of recommendation C, level of evidence 3) demonstrated a 33 % response rate [115]. Combined instillation of hyaluronic acid and chondroitin sulfate in refractory interstitial cystitis resulted in significant symptomatic improvement [116]. Botulinum toxin (grade of recommendation C, level of evidence 4) inhibits the release of calcitonin gene-related peptide and substance P from afferent nerves, thus decreasing pain. Small studies of intravesical Botox into the bladder wall reported symptom relief in IC patients , without significant adverse events [117].
5.12.3.3 Pain Modulation
Tricyclic antidepressants (TCAs), especially amitriptyline, are known to have pain-reducing effects (grade of recommendation B, level of evidence 2). One recent RCT of amitriptyline evaluated 50 patients with IC. Improvement in overall symptom scores, as well reduction in pain and urgency, were significantly greater in the treatment group (P < 0.001) (Tables 5.2 and 5.3) [118].
Table 5.2
Oral medications for treatment of BPS/IC: results
Drug | RCT | Success (%) |
|---|---|---|
Amitriptyline; tricyclic antidepressant | Yes | 42 |
Antibiotics | Yes | 48 |
Cimetidine | Yes | 65 |
Hydrocortisone | No | 80 |
Cyclosporin | No | 90 |
Hydroxyzine | Yes | 31 |
l-Arginine | Yes | Not effective |
Nifedipine | No | 87 |
Quercetin | No | 92 |
Sodium pentosan polysulfate | Yes | 33 |
Suplatast tosilate | No | 86 |
Table 5.3
Intravesical medications for treatment of BPS/IC: results
Drug | RCT | Success (%) |
|---|---|---|
DMSO | Yes | 70 |
BCG | Yes | Conflicting RCT data as to efficacy |
Resiniferatoxin
Related posts: Overactive Pelvic Floor: Gastrointestinal Morbidities
Female Voiding Dysfunction
 The Pelvic Floor and Male Sexual Function
 Female Genital Pain and Penetration Disorders
 A Tale of Two Pain States: The Integrative Physical Therapy Approach to the Overactive Pelvic Floor
 Complementary and Alternative Therapies for the Overactive Pelvic Floor
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