Painful Bladder Syndrome’s Diagnostic and Therapeutic Controversies: A Review

Painful Bladder Syndrome (PBS) is a controversial disease with no consensus on its nomenclature, diagnostic criteria, or aetiology. Interstitial Cystitis (IC), PBS, chronic pelvic pain syndrome, and Hypersensitive Bladder Syndrome (HBS) are closely related clinical diseases. Hence, underdiagnosis or misdiagnosis of PBS and consequent failure of disease management may occur. This review aims to explore the established and emerging controversies regarding the epidemiology, aetiology, pathogenesis, pathophysiology, clinical presentation, diagnostic criteria, workup and management strategies of PBS. A literature search was carried out in the following electronic databases, PubMed, Scopus, Embase, Google Scholar, Directory of Open Access Journals and Cochrane electronic databases from starting of May to first week of June 2020. Keywords including Bladder Pain Syndrome (BPS), aetiology, histopathology, management and diagnosis were used to search these various databases. Accurate data on the prevalence of PBS is scarce, primarily as there is no standardised definition. Furthermore, there are there no fixed criteria for diagnosis, leading to variability in the reported prevalence of PBS in the literature. Management approaches in patients with PBS must be individualised and tailored to each case in terms of aetiology, diagnosis, and treatment.

The IC is a disease of an intricate nature that is rife with controversies, beginning with the fact that no scientific consensus on its naming, diagnostic criteria, aetiology, or management exists. IC, PBS, BPS, chronic pelvic pain syndrome and HBS [1,2] are all diagnoses that share many characteristic storage symptoms: urgent urination, nocturia, frequent urination and painful or unpleasant bladder sensations that improve with emptying. There is a wide variety of diagnostic criteria, depending on which organisation’s definition of the disease is used. One primary difference in these criteria is the duration of symptoms: six weeks is specified in the American Urological Association (AUA) guidelines and six months in European Association of Urology (EAU) guidelines. In addition, cystoscopy is optional according to the AUA, but not according to the EAU [3-5]. Another difference is in the strictness of the criteria; the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has the strictest guidelines, with 18 exclusionary criteria [Table/Fig-1] [4]. The NIDDK definition of IC as intended for research purposes states that the patient should not have any of the exclusionary criteria [Table/Fig-1], and must have either glomerulations that appear during cystoscopy, bladder distention to 80-100 cm of water pressure for two minutes under regional or general anaesthesia, petechial haemorrhaging appearing in three to four quadrants of the bladder, or Hunner’s ulcers on cystoscopy, in addition to urgency or bladder pain with filling [4].

The International Society for the Study of BPS defines IC as chronic pelvic pain, discomfort, or pressure related to the bladder, with at least one urinary symptom such as urgency or frequency and with other diseases excluded by proper workup, including cystoscopy and bladder biopsy [6]. They define BPS as chronic bladder pain lasting for at least six months, with frequency and nocturia. Furthermore, pain must be related to bladder filling, increasing with volume and decreasing with emptying and be suprapubic with possible radiation to another pelvic organ, including the sacrum [5]. To help reduce variations in practice and outcome, this review explores the established and emerging controversies regarding the epidemiology, aetiology, pathogenesis, pathophysiology, clinical presentation, diagnostic criteria and work up, and management strategies of PBS.

In one study in a small region of Finland, the prevalence of PBS was estimated to be 10.1 cases per 100,000 people in 1975 [7], compared with 30 per 100,000 (0.03%) in 1987 and 510 per 100,000 (0.5%) in 1994 in the United States [8]. The criteria for a diagnosis of IC included a history of chronic lower urinary tract symptoms (mainly voiding) and a bladder biopsy showing fibrosis, edema and/or lymphocytic infiltration, in addition to sterile urine [7].

Clemens JQ et al., demonstrated that the prevalence of PBS differs between males and females, ranging from 16.5 cases per 100,000 males to 224 cases per 100,000 females [9], with an increasing prevalence in females with a first-degree relative with PBS [10]. Peters KM et al., reported in their study that 25% of adults with PBS have complained of PBS symptoms since childhood [11].

The strict inclusionary and exclusionary criteria recommended by the NIDDK, misses the diagnosis of at least 60% of patients with a high likelihood of having IC [12]. Moreover, the aetiology of the disease is not well-understood. Although some theories have been proposed, they have failed to find a statistically significant difference between patients with PBS and control groups. Birder LA recently published an article on the pathophysiology of PBS, finding that the activation of the P2X3 purinoceptor can lead to an increase in the bladder afferent response after the release of ATP from the urothelium, which might lead to a new modality of treating PBS using a P2X3 purinoceptor blocker [13].

The Antiproliferative Factor (APF) is a unique protein that inhibits the proliferation of bladder cells which leads to bladder thinning and affects the bladder barrier [14,15]. In addition, the level of the heparin-binding epidermal growth factor, which is important in the epithelial repair process, is decreased by APF [16]. The autoimmunity theory is based on the difference in bladder urethral cells between patients with PBS and control groups. Patients with PBS have more CD41, CD81, B lymphocytes, immunoglobulins (IgA, IgG, and IgM), and plasma cells than control patients [17-19].

The central sensitisation of the spinal cord theory explains why PBS patients have pain even after cystectomies, as the sensitisation of the lower spinal cord is a chronic pain syndrome that leads to sensitisation in the pelvic organs such as the bladder [20]. Recently, Jhang JF et al., suggested a new theory related to the alteration of bladder Corticotropin-Releasing Hormone Receptors (CRHRs) in patients with PBS. CRHR staining has shown that CRHR1 is primarily expressed in the submucosa and CRHR2 is primarily expressed in urethral cells [21].

The histopathological diagnosis of PBS is based on exclusion of other possible diagnosis like eosinophilic cystitis, carcinoma in-situ and others [22,23]. There is no consistent histological features pathognomonic of PBS and variations are observed in histological findings of biopsies done on different patients with PBS and also biopsies repeated in same patients over a period of time [3]. Distinct histological findings are reported in ulcerative and non-ulcerative IC. A study involving 64 patients in ulcerative disease group and 44 patients with non-ulcerative disease group reported intense inflammatory infiltration with more number of mast cells, haemorrhage and granulation tissue in ulcerative group whereas the non-ulcerative disease group had multiple suburothelial haemorrhages with sparse infiltration [24].

According to most recent studies, PBS can affect all ages, and the mean age at diagnosis ranges from the 40’s to early 50’s. In one survey study, the age at diagnoses of over 3397 women ranged from 18 to 92 years, with a mean age of 45.7 years [25]. Another study on the Danish population showed that the age of presentation ranges from 16 to 88 years, with a mean age of 53 years [26].

Symptoms in females of age 30-year-old or younger primarily include urgency, frequency, dysuria and dyspareunia, whereas some present with nocturia and vulvar pain. In patients over 30 years of age, the primary symptom is nocturia, which increases with age [4].

Nocturia and pelvic pain in young women should raise suspicions of PBS. Additionally, dyspareunia is reported in more than 60% of young women with PBS. The pain is not specific to intercourse and can happen in the genital area without or after intercourse [27]. Most patients with PBS report pain located in the bladder (88%), urethra (16%), genitals (3%), and non-genital areas (3%) [28].

Chronic fatigue

Nickel JC et al., observed chronic fatigue in 9.5% of patients with PBS, compared with 1.7% in the control group [19]. Another study on twins reported that a fatigued twin is 20 times more likely to have PBS than their non-fatigued twin [29]. Warren JW et al., reported that the odds ratio of IC occurring with chronic fatigue syndrome is 2.5, which is the same as all chronic pain syndromes. They noted that chronic fatigue might be a risk factor for PBS [30].

Fibromyalgia

Rodríguez MA et al., reported that 9% to 12% of patients with PBS have symptoms of fibromyalgia, and 2.25% to 27% of patients with fibromyalgia have symptoms of PBS [29]. In a study from Michigan, the odds ratio of diagnosing fibromyalgia in patients with PBS was 5.1 [31]. In a case-control study, Warren JW et al., compared 313 patients with PBS symptoms to a control group to evaluate their risks of fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and sicca syndrome. Seventy-eight percent of patients with PBS had more than two diseases, compared with 45% in the control group [32].

Irritable bowel

Rodríguez MA et al., reported that between 7%-48% of patients with PBS or symptoms of PBS have an irritable bowel, and the patients with IC are 11 times more likely than control group patients to be diagnosed with an irritable bowel [29].

Pelvic inflammatory disease

Chung SD et al., reported that there is a correlation between PBS and pelvic inflammatory disease, which is an inflammatory gynaecological disease associated with tubo-ovarian abscesses. In their case-control study, the prevalence of pelvic inflammatory disease in PBS cases and controls was 41.7% and 15.4%, respectively (p<0.001) [33].

The treatment options range widely from dietary modification as a first-line therapy to surgical reconstruction and diversion as a sixth-line approach. The treatment options outlined by the Actual Ultrasound Date (AUA) are presented below [34].

Dietary modification

The fact that some foods irritate the bladders of patients with PBS is supported by many questionnaire-based studies [35,36]. Shorter B et al., found that 90% of patients with PBS report sensitivity to one or more types of food [37]. Citrus fruits, tomato products, alcohol, cola, and Mexican and Thai foods were the most common bladder irritants for patients with PBS. However, Fisher B et al., failed to find a statistical association between PBS and diet in a placebo-controlled study [38]. As dietary modification has a very low risk, it is recommended as an early management therapy option for patients with PBS [39].

Pelvic floor physical therapy

Fitzgerald MP et al., reported levator pain on examination in 87% of 70 women with PBS [4]. Schmidt RA and Vapnek JM noted that the pain appeared to be associated more with changes in sphincter tone than in detrusor muscle changes in the urodynamic testing of patients with PBS [40]. Physical therapy or trigger-point release is a valid treatment modality for patients with PBS. Weiss JM reported that 83% of patients with PBS improved markedly or completely with respect to bladder pain after 8–12 weeks of pelvic floor physical therapy, as documented by a 65% decrease in the resting pelvic floor pressure on an electromyography [41]. Owing to the low risk of pelvic floor therapy and evidence of improvement in patients with PBS, pelvic floor physical therapy is recommended as an early management modality for PBS [42].

Oral therapy

The oral therapeutic options for PBS include PPS, amitriptyline, cimetidine, hydroxyzine, immunotherapy, and cyclosporin A.

PPS is a semi-synthetic chemical structure that produces a heparin-like macromolecular carbohydrate derivative similar to that found in the GAG layer of the bladder [43]. PPS replaces the deficit part of the GAG layer and decreases the permeability of solutes into the nerve endings, which, in theory, leads to an improvement in PBS symptoms, particularly pelvic pain [44,45].

The therapeutic application of amitriptyline in urology is secondary to its central sedative activity, anticholinergic effect, antihistamine effect, and serotonin and noradrenaline re-uptake inhibition activity [46], and may be due to the effect of amitriptyline on the limbic pain center of the brain, which is usually up-regulated in patients with pelvic pain [46]. The recommended dose is 25-100 mg, but it must be titered according to improvements in symptoms. The side effects of amitriptyline increase with higher doses and include drowsiness, dry mouth, constipation, fatigue and malaise [47].

Cimetidine is a histamine H2-antagonist and is commonly used to treat peptic ulcers. Seshadri P et al., reported an improvement of symptoms after the oral administration of 300 mg of cimetidine twice daily in six of nine (66.67%) patients with PBS; four of these patients reported a complete and sustained improvement [48].

Hydroxyzine is an oral anti-allergic medication that blocks H1 receptors [49]. It is commonly used for urticaria and allergic rhinitis [50]. Patients with PBS are more prone to allergies than the general population [51]. Theoharides T and Sant GR reported a 40% improvement in PBS symptoms with hydroxyzine. The side effects of hydrazine include sedation and drowsiness, urine retention and an increased appetite [52]. The standard dose of hydrazine is 25 mg at bedtime, titered to 75 mg daily. Given the low severity of the adverse effects of hydrazine, it is recommended as a second-line therapy [42].

There has been some evidence regarding improvement in PBS symptoms following the administration of immunotherapy medication, which may be explained by the fact that some patients with PBS might have autoimmune dysregulation [53-55]. Moran PA et al., studied the therapeutic effect of methotrexate in the management of refractory BPS, which produced a significant reduction in the pain score. However, there was neither an improvement in the voided volume nor a change in the frequency of symptoms [53].

Cyclosporin A is a calcineurin inhibitor and inhibits the activation of T cells [56]. Sairanen J et al., reported the results of a randomised study comparing the efficacy of PPS versus Cyclosporin A in patients with PBS, which showed a superior response with cyclosporin A [57]. Forrest JB et al., reported the outcome of cyclosporin A in refractory PBS: The GRA was 85% in Hunner’s ulcer PBS compared with 30% in non-Hunner’s PBS. The adverse effects of cyclosporin A (1.5 mg/kg twice daily) include renal impairment, an increased blood pressure and infection [58].

Intravesical therapy is used in patients with PBS to restore the GAG layer, as with heparin [59], or for its anti-inflammatory properties and its ability to inhibit angiogenesis and fibroblast proliferation [60]. Considering the low severity of adverse effects, AUA guidelines recommend intravesical heparin, sodium bicarbonate, and lidocaine as a second-line therapy for PBS [42].

DSMO is a wood-pulp industry material first synthesised in 1867 [61,62]. It has some bacteriostatic activity and analgesic and anti-inflammatory effects [63]. Perez-Marrero R et al., reported the results of a study on treating PBS with DSMO versus a placebo [63]. DSMO is administered intravesical once every week for 4 to eight weeks [64], and the response has been documented to last for one year [65]. The adverse effects of DSMO are mild and primarily related to bladder irritation, a garlic-like taste, and headaches [66]. Considering the low severity of adverse effects, AUA guidelines recommend intravesical DSMO as a second-line therapy [62].

Cystoscopy with short-duration hydrodistension

Cystoscopy of patients with PBS is essential for ruling out other causes of storage symptoms such as bladder tumours or carcinoma in-situ [67]. However, it is well-established that not all patients with PBS will have a positive finding under cystoscopy [68]. There is some evidence, based only on observational studies that hydrodistension is beneficial for PBS [69-71].

Hunner’s ulcer fulguration

The presence of a Hunner’s ulcer is one of the criteria used to diagnose PBS, based on the NIDDK guidelines. Hillelsohn JH et al., reported the results of a retrospective study of fulguration in 59 patients with PBS with Hunner’s ulcers. Seventy-eight percent reported sustained improvement and almost half required repeated fulguration sessions with a 4-year follow-up [72]. A neodymium-yttrium-aluminum-garnet laser or injection with triamcinolone can be used instead of fulguration, and treatment sessions have been documented to last for up to one year [73,74]. AUA guidelines consider cystoscopy with Hunner’s ulcer fulguration, a laser, or a triamcinolone injection to be a third-line therapy for patients with PBS [42].

Intravesical Onabotulinumtoxin A

Onabotulinumtoxin A is a strong toxin derived from Clostridium botulinum which inhibits neurotransmitter release (primarily acetylcholine) at the neuromuscular junction, ultimately causing muscle paralysis [75]. Lee HY et al., recently reported the results of a meta-analysis of 248 patients over six trials on the safety and efficacy of intravesical onabotulinumtoxin-A in treating an overactive bladder. Only the voided volume significantly improved, and all other parameters of overactive symptoms and bladder pain were insignificantly changed [76]. The most common adverse effects of intravesical onabotulinumtoxin-A injection are urine retention, urinary tract infections, haematuria, a high pulmonary vascular resistance, and complications of clean intermittent catheterisation [77]. Considering the side effects and the expected improvement with an intravesical injection of onabotulinumtoxin-A, AUA guidelines recommend intravesical onabotulinumtoxin-A as a fourth-line treatment for patients with PBS [42]. [Table/Fig-2] shows dosage of various therapeutic agents used in PBS.

Neuromodulation

Abnormal pain signals and C-fiber activities constitute one of the proposed aetiologies of PBS [33]. Sacral neuromodulation might block C-afferent-fiber activity [78] and has been shown to alter the level of heparin-binding epidermal growth factor and APF in patients with PBS [79]. Wang J et al., published a meta-analysis of sacral neuromodulation used to treat PBS, in which a total of 583 patients were included in 17 studies, and the success rate was 84%, with minimal adverse effects. All PBS parameters significantly improved, including the frequency, nocturia, symptom index scores, voided volume, and urgency [80]. Percutaneous Tibial Nerve Stimulation (PTNS) has been investigated in patients with PBS. O’Reilly B et al., found no difference in the pain scale between the treatment group and the control group [81], whereas Gokyildiz reported an improvement in the pain scale and quality of life scores of the PTNS group [82]. The AUA guidelines recommend neuromodulation as a fourth-line treatment for patients with PBS [42].

Surgical reconstruction/urinary diversion

The last solution to consider for patients with PBS is major surgical construction and urinary diversion. The consideration of this procedure depends on the patient and the surgeon’s experience, and includes an ileal conduit, supratrigonal cystectomy, ileocystoplasty, continent urinary diversion (Kock pouch), continent orthotopic diversion, or cecocystoplasty. These surgeries are reserved for refractory PBS resistant to all other treatments or for patients with a small bladder capacity on hydrodistension (less than 300 mL) [83]. AUA guidelines recommend surgical reconstruction and urinary diversion as a sixth-line and final option in treating patients with PBS [53].

PBS is a disease that causes conflict among investigators and has no standardised definition or diagnostic criteria. Moreover, there is no definitive aetiology for PBS. In addition, according to the AUA guidelines, there are six lines of treatment starting with behavioural modification and ending with major surgery for urinary diversion. This review recommends that further education for the general population, general urologists, and family physicians on PBS and its management is needed.

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