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International Journal of Urology (2014) 21 (Suppl 1), 49–55
doi: 10.1111/iju.12317
Review Article Potential therapeutic effect of intravesical botulinum toxin type A on bladder pain syndrome/interstitial cystitis Jia-Fong Jhang, Yuan-Hong Jiang and Hann-Chorng Kuo Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan
Abbreviations & Acronyms ATP = adenosine triphosphate AUA = American Urological Association BCG = bacillus Calmette–Guérin BoNT-A = botulinum toxin type A BPS/IC = bladder pain syndrome/interstitial cystitis CPSI-F = Chronic Prostatitis Symptom Index (female modification) ESSIC = European Society for the Study of Interstitial Cystitis FD vol = first desire to void volume HAM-A = Hamilton Anxiety Rating Scale HRQL = health-related quality of life ICPI = Interstitial Cystitis problem index ICSI = Interstitial Cystitis Symptom Index KHQ = King’s Health Questionnaire LOE = level of evidence MCC = maximum cystometric capacity NGF = nerve growth factor Pdet = maximal detrusor pressure Qmax = maximal urinary flow rate SF-36 = 36-item Medical Outcomes Study Short Form VAS = visual analog scale Correspondence: Hann-Chorng Kuo M.D., Department of Urology, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan. Email: [email protected]; [email protected] Received 17 July 2013; accepted 14 August 2013.
© 2014 The Japanese Urological Association
Abstract: Bladder pain syndrome/interstitial cystitis is characterized by bladder pain associated with urgency, frequency, nocturia, dysuria and sterile urine. Recent studies have shown that these bladder dysfunctions could originate from chronic inflammation or urothelial insult and proceed to a cascade of tissue reactions, which finally ascends to the central nervous system. Pilot studies of intravesical injection of botulinum toxin type A for bladder pain syndrome/interstitial cystitis had been introduced since 2005 with a promising result. Recent evidence suggests that botulinum toxin type A could significantly improve symptoms such as daytime frequency, nocturia, pain, quality of life and bladder capacity in bladder pain syndrome/interstitial cystitis patients. Single injection of botulinum toxin could not achieve long-term successful therapeutic result, and repeat injections could provide a better long-term success rate. However, patients with ulcer type bladder pain syndrome/ interstitial cystitis might not gain a benefit from botulinum toxin type A injection. Laboratory evidence showed that botulinum toxin type A for bladder pain syndrome/interstitial cystitis injection could induce peripheral desensitization, reduces bladder chronic inflammation and decreases apoptotic signal molecules in the urothelium. The present article reviewed the recent advances of botulinum toxin type A on bladder pain syndrome/ interstitial cystitis. Key word: bladder pain syndrome, botulinum toxin, interstitial cystitis.
Introduction BPS/IC is a syndrome of mystery in urology, and the pathophysiology of BPS/IC has not been fully understood. The clinical characteristic of BPS/IC is severe bladder pain associated with urgency, frequency, nocturia, dysuria and sterile urine. The diagnosis of IC/BPS is based on the symptoms and clinical urological findings, including characteristic cystoscopic features after hydrodistention under anesthesia.1 The National Institute of Diabetes and Digestive and Kidney Diseases criteria have been used to select more uniform patients for clinical research,2 and is today widely used in Asia for the diagnosis of IC.3 O’Leary proposed the ICSI and ICPI to measure lower urinary tract symptoms and their impact in 1997, and it is widely used in many studies now.4 Although many pathogeneses of IC/BPS have been proposed, the actual etiology remains unclear.5 The possible etiologies of IC/BPS include neurogenic inflammation, postinfection autoimmune process, mast-cell l activation and urothelial dysfunction.5–8 As the pathogenesis of BPS/IC remains unclear, the current goals of treatment are largely based on symptomatic relief. Cystoscopy with hydrodistention and biopsy is the first choice for diagnosis, classification and treatment. In a prospective study including 33 patients that underwent hydrodistention, the median symptom score for patients decreased after distention, but just 12 patients (36%) had at least 30% symptom improvement.9 Oral pentosan polysulfate sodium, hydroxyzine, amitriptyline, prednisone, cyclosporin, intravesical hyaluronic acid and heparin were carried out to treat BPS/IC, but the therapeutic result was controversial.10 Currently, BPS/IC does not have standard treatment.11 BoNT is one of the most powerful neurotoxins that inhibits the release of neurotransmitters from nerve fibers and the urothelium.12,13 It is widely used for medical purposes. The application of BoNT-A for the treatment of lower urinary tract symptoms was initiated in the late 1980s. Dykstra et al. described injections of BoNT-A into the external urethral sphincter in spinal cord injury patients to induce chemical sphincterotomy and treat detrusor sphincter dyssynergia.14 Intravesical BoNT-A injection has been used in patients with BPS/IC since 2004. The study reported that nine (69%) of 13 patients noted subjective improvement after BoNT-A treatment, and the symptoms score improved by 71%.15 Recently, many studies have discussed intravesical BoNT-A in BPS/IC, and it seems to have a promising result. We reviewed the possible patho49
J-F JHANG ET AL.
genesis of BPS/IC, and discussed the therapeutic mechanism, results, and adverse effects of intravesical BoNT-A injection in the present article.
Possible pathogenesis of BPS/IC The possible pathogenesis of BPS/IC had been widely discussed in the past 100 years. The most prevalent histology findings of bladder biopsy specimens in BPS/IC are denuded epithelium, mucosal ulceration, submucosa granulation tissue, and inflammatory and perineural infiltrate.16 These findings suggest an inflammatory process in the bladder, but the actual pathophysiology is still unknown. Recent studies have suggested that several pathophysiological mechanisms, including epithelial dysfunction, activation of mast cells, cell apoptosis, are involved in BPS/IC.17,18 The hypothesis of neuroimmune inflammation mediating the pathophysiology of BPS/IC has recently triggered heated discussion. An increase of the submucosal nerve fiber proliferation was found in BPS/IC bladder tissue, but it was not found in patients with bacterial or lupus cystitis.19 Lundeberg et al. also found increased mast cell count, histamine and nerve fibers in patients with BPS/IC. There was a good correlation between the number of nerve fibers and number of mast cells, as well as between the number of nerve fibers and the amount of histamine.20 Some substances released from neurons have been shown to induce mast cell secretion, and the mast cell–nerve interaction is well identified in human intestinal nociception.21 Substance P, a neuropeptide associated with inflammatory processes and pain, is thought to mediate mast cell accumulation, activation and degranulation. It could result in nociceptive sensitization.22 Substance P-containing nerve fibers were present in the bladder submucosa tissue of patients with BPS/ IC.23 That study suggested that a neuron-mediated inflammation process might be implicated in the pathophysiology of pain in BPS/IC, and has been shown to trigger mast cell secretion. Recent evidence also showed that urothelium apoptosis plays an important role in the pathogenesis of BPS/IC. By electron microscopy, an increased number of apoptotic urothelium with morphological changes of nuclear fragmentation in the bladder of BPS/IC had been identified.24 The percentage of Annexin V binding, an early apoptosis marker, was also significantly higher in bladder endothelial cells from BPS/IC patients with pain than control patients (P < 0.01). Our previous study investigated cell proliferation and apoptosis in the BPS/IC bladder.25 The ratio of ki-67-positive cells (to assess cell proliferation) was significantly downregulated, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining significantly increased in the bladder tissue of BPS/IC patients. Our further study suggested bladder inflammation could directly modulate the signaling pathway and increased urothelial cell apoptosis in BPS/IC. Protein antibody array and western blotting study showed that pro-apoptotic proteins including Bax, Bad, cleaved caspase-3 and phospho-p53 level were greater than those for the controls.18 Immunofluorescence staining of phospho-p38 were also positive in the urothelium of the patients with BPS/IC. Our evidence suggested abnormal and aggressive apoptosis might participate in the pathophysiology of BPS/IC. Neural upregulation might also participate in the pathophysiology of BPS/IC. Mechanoreceptors and chemoreceptors in the 50
bladder could trigger myelinated A-δ fibers or C-fibers in the smooth muscle or the submucosa in response to bladder distention.26 It is postulated that distention of the bladder causes release of ATP from epithelial cells. Released ATP can activate ligand-gated ion channels P2X3 receptors (purinoceptors) on nerve terminals in bladder urothelium or muscle, and evoke a neural discharge.27,28 Previous immunochemical evidence showed significant upregulation of the P2X3 receptor in BPS/IC bladder urothelial cells than normal controls.29 In cyclophosphamide-induced cystitis rat, a significant increase in the expression of substance P and calcitonin gene-related peptide was found in the L6-S1 spinal segment and dorsal root ganglia.30 No changes were observed in the L4-L5 spinal segment or dirsal root ganglion. Bladder pain also can be induced by activation of capsaicin-sensitive, unmyelinated afferent nerves.31,32 The transient receptor potential cation channel subfamily V member 1 (TRPV1) is the receptor of capsacin, and the increased mRNA expression of TRPV1 was found in bladder tissue of interstitial cystitis.33,34 In a cat animal model, dorsal root ganglion neurons (L4-S3) in the cat with BPS/IC showed increased neuron number and exhibited capsacin responses, which are increased in amplitude and desensitize slowly.35 This study suggested bladder inflammation could result in alterations in the neuropeptide expression in the central nerve system. Increasing excitability and sensitization of bladder afferent nerves could contribute to an increasing abnormal pain sensation with bladder distention.26 Although it is still unclear whether neural mechanisms and inflammation are the cause of BPS/IC, it is evident that neural upregulation plays a role in pain, urgency and frequency. Therapy for BPS/IC should act to regulate neural reaction, improve abnormal urothelial apoptosis and control inflammation.
Biology and mechanism of botulinum toxin BoNT is a protein and neurotoxin produced by the bacterium, Clostridium botulinum, and it was identified more than 100 years age.36 It has a 50-kd light chain and a 100-kd heavy chain, and seven immunologically distinct neurotoxins (types A to G) are produced by different C. botulinum strains. In culture fluid and food with acidic conditions, the botulinum neurotoxins associate with non-toxic components, and form large complexes designated as progenitor toxins. The progenitor toxins are found in three forms: 19S, 16S and 12S, and they are composed of neurotoxin, hemagglutinin and non-toxic nonhemagglutinin.37,38 The neurotoxin of BoNT is initially biologically inactive until it is activated by proteolytic cleavage into a 100-kDa heavy chain and a 50-kDa light chain.39 BoNT-A progenitor toxins have been used for treating patients with strabismus, blepharospasm and nystagmus.40 It has been marketed as Botox (onabotulinumtoxinA) in the USA (Allergan, Irvine, CA, USA) and as Dysport (abobotulinumtoxininA) the UK (Ipsen, Slough, Berkshire, UK). BoNT recognizes and enters neurons by binding to the synaptic vesicle protein, SV2, during neurotransmitter exocytosis when more active receptors are exposed.41 Through endocytosis of this toxin, the disulphide bond is cleaved. The light chain is the true active moiety of the molecule, and can combine with SNAP-25 protein to inhibit exocytosis of the acetylcholine © 2014 The Japanese Urological Association
Botulinum toxin on interstitial cystitis
from the vesicles. The affected neuromuscular junctions become paralyzed after injection of BoNT.42 Although BoNT is known to show cholinergic specificity, release of other transmitters can be inhibited. Smith et al. found that intravesical injection of BoNT-A could inhibit ATP release from the urothelium on bladder contraction.43 In a chronic spinal cord injury rat model, BoNT-A injection also could normalize ATP and nitric oxide release from urothelium.44 Recent studies in rats showed that BoNT-A inhibited sensory neuropeptide release, including substance P and calcitonin gene-related peptide, from isolated rat bladder preparations after cyclophosphamide-induced inflammation, suggesting that BoNT-A had a potential clinical benefit in the treatment of neurogenic inflammation.45 BoNT-A injection in surgical wounds on a rat resulted in less infiltration of inflammatory cells than the control group at the second week, and there was a lower transforming growth factor beta1 expression in the BoNT-A group.46 This result suggested that BoNT injection might control local tissue inflammation.
Intravesical BoNT-A in BPS/IC Pilot studies reporting the efficacy of BoNT-A for treating BPS/IC since 2004 have shown controversial results. Smith et al. reported 13 female patients with BPS/IC received BoNT-A 100–200 U into 20–30 sites submucosally in the trigone and floor of the bladder with hydrodistention at the same time.15 The ICSI and ICPI mean scores in these patients improved by 71% and 69%, respectively (P < 0.05). Daytime frequency, nocturia and pain by visual analog scale also decreased by 44%, 45%, and 79%, respectively (P < 0.01). The onset of symptom relief was 5–7 days after treatment, and the mean duration of symptom relief was 3.7 months. Our preliminary study of BoNT-A in BPS/IC was carried out in 2005, and 10 patients with BPS/IC who had failed conventional treatments were enrolled in this study.47 In 10 patients, 100 U of BoNT-A was suburothelially injected into 20 sites, and an additional 100 U was injected into the trigone of 5 of these patients. Just two patients’ bladder pain and urinary frequency were improved at 3 months after treatment, and the five patients that received trigonal injection had no therapeutic effect on symptoms or urodynamic improvement. Giannantoni et al. reported her series of BPS/IC patients who received BoNT-A injection and were followed since 2006.48 In that study, 200 U of BoNT-A was injected submucosally in the trigone and bladder floor under. Approximately 80% of patients reported a subjective improvement at 1 month after therapy. Mean VAS scores, and mean daytime and night-time urinary frequency decreased significantly compared with pretreatment. The most recent studies support the promising therapeutic effects of BoNT-A in patients with BPS/IC. Ramsay et al. carried out a prospective study of 11 patients with BPS/IC that received 200–300 U BoNT-A, and found it could improve symptoms scores by 20% in 14 weeks after treatment.49 Giannantoni et al. reported her 1-year follow-up report of BoNT-A injection in BPS/IC; patients showed significant improvement of VAS scores and frequency at 1-month and 3-month follow up.50 Giannantoni et al. also used the HAM-A and the SF-36 to evaluate psychological function and quality of life in 14 BPS/IC patients who received BoNT-A injection. At the 3-month follow up, patients showed significant improvement of anxiety, depres© 2014 The Japanese Urological Association
sion and quality of life.51 We designed a prospective and randomized control study in 67 patients with refractory BPS/ IC.52 A total of 44 patients received suburothelial BoNT-A injection with 200 U or 100 U in 2 weeks after cystoscopic hydrodistention, and 23 patients received cystoscopic hydrodistention alone. At 3 months after treatment, the improvement of the VAS score, and functional and cystometric bladder capacity increases were significant only in the BoNT-A groups. A successful therapeutic result at 6, 12 and 24 months was reported in 31 (71%), 24 (55%) and 13 (30%) patients in the BoNT-A groups, respectively. The successful therapeutic result rate in BoNT-A groups at 12 and 24 months was significantly better than it in the cystoscopic hydrodistention group. BCG instillation therapy for BPS/IC was also compared with BoNT-A injection.53 The improvement of pelvic pain, frequency urgency and nocturia in the BoNT-A injection group was significantly better than it in the BCG instillation group. Our recent prospective study that enrolled 67 patients is currently the largest series of BoNT-A single injection in refractory BPS/IC.54 The patients received 100 U BoNT-A suburothelial injection to 40 sites with cystoscopic hydrodistention, and were followed every 3 months. The ICSI, ICPI, O’Leary–Sant Score, VAS, frequency, nocturia, functional bladder capacity, cystometric bladder capacity and global response assessment were significantly improved in the patients at 3-month and 6-month follow up. We suggested 100 U BoNT-A intravesical single injection is effective in relief of bladder pain and lower urinary tract symptoms at short-term follow up. The results of clinical studies for the use of BoNT-A in BPS/IC are listed in Table 1.
Repeat BoNT-A injections Although BoNT-A injection provides symptomatic relief in treating BPS/IC, long-term therapeutic effects have not been achieved after single injections. Giannantoni et al. reported that 11 of 15 patients with BPS/IC who had received BoNT-A injection had bladder pain recurrence at 5 months after treatment. Bladder pain had recurred in all cases at 1-year follow up.50 In our series, patients who received a single BoNT-A injection with cystoscopic hydrodistention had just 55% and 30% successful therapeutic results at 12- and 24-month follow up, respectively.52 Giannantoni et al. reported 13 women with BPS/IC who received repeat BoNT-A 200 U injection with a mean of 4.8 ± 0.8 injections per patient.55 The mean interval between two consecutive injections was 5.25 ± 0.75 months. The mean VAS scores, and mean daytime and night-time urinary frequency had persistently significantly decreased compared with pretreatment at 1-month, 4-month, 5-months, 1-year and 2-year follow up. The maximum cystometric capacity also had a persistently significant improvement. We also carried out a study to investigate the clinical efficacy of repeat BoNT-A injections.58 A total of 81 patients with refractory BPS/IC received suburothelial injection of BoNT-A 100 U to 40 sites. Repeat BoNT-A therapy was recommended at 6 months after the initial treatment if patients felt a relapse of baseline symptoms or desired repeated treatment to achieve a better treatment outcome. The procedure was repeated every 6 months up to four times, or until patients declared their symptoms had significantly resolved or patients did not want repeated treatment 51
52
13
10
14
11
15
15 29 23 16 16 13
26
14
20
67
81 30
Smith et al. 200415
Kuo, 200547
Giannantoni et al. 200648
Ramsay et al. 200749
Giannantoni et al. 200850
Kuo and Chancellor 200952
Pinto et al. 201056
Giannantoni et al. 201051
Gottsch et al. 201157
Chung et al. 201254
Kuo, 201358
24 mo
6 mo
3 mo
3 mo
3 mo
22 wks 23 wks 24 mo
3 mo
3 mo
14 wks
3 mo
3 mo
3 mo
Follow up
100 U, 20 mL, 1 injection 100 U, 20 mL, 4 injections
100 U, 20 mL
50 U, 2 mL, Botox Placebo, saline 2 mL
200 U, 20 mL, Botox
200 U 20 mL Botox + HD 100 U 20 mL Botox + HD HD BCG 300 U Botox Repeat mean 4.8 times injections/patient 200 U, 20 mL, Botox 100 U, 10 mL, Botox
200–300 U, 20–30 mL, Botox 200 U, 20 mL, Botox
100–200 U, 10–20 mL, Botox or Dysport 100–200 U, 10–20 mL, Botox 200 U, 20 mL, Botox
BoNT-A preparation (dose)
Δ%: change from baseline, percentage. *Significant improvement for baseline.
Giannantoni et al. 201055
El-Bahnasy et al. 200953
n
Clinical studies for the use of BoNT-A in BPS/IC
Authors, year
Table 1
– −47%* – −56%* −51% −24% −5% –54%* –100%* −58.4%*
−62%* −74%*
−25%* −35%* −33% −43%* −34%* −25% −14% −31% −68%* −51%*
−59%*
20 sites, bladder floor and −56%* trigone 2 sites, periurethral injection at 3 & 9 o’clock, in the region of the bladder neck, 40 sites, bladder floor −31%* except trigone 40 sites, bladder floor −23%* except trigone −21%*
10 sites, trigone only
– – 20 sites, bladder floor and trigone
20 sites, bladder floor and trigone 40 sites, bladder floor except trigone
63%*
90%*
163%*
–
62%* 26%* 4%
38%*
29%
30%*
27%*
57%*
MCC (Δ%)
−46%*
−71%*
−55%* −39%* −18% −81%* −96%* −39.1%*
−28%*
–
−34%*
−25%*
−79%*
VAS (Δ%)
40%* 17% 9%
27%*
77%*
–
144%*
–
–
50%*
58%*
FD vol (Δ%)
–
−66, −56%*
−42, −36%* −38, −35%* −23, −23%* –
–
–
–
–
−69, −71%*
ICPI, ICSI (Δ%)
−28% −16%
12%* 18%*
−30%* −37%*
26%* 65%*
−28, −27%*
No significant inter-or intragroup improvements in CPSI-F, AUA Symptom Index, Graded Chronic Pain Scale, Perceived Stress Scale and VAS −36%* 8% −37%* 32%* −38, −34%*
−45%*
−44%*
20–30 sites, trigone and bladder floor 20–30 sites, Bladder floor only or with trigone 20 sites, bladder floor and trigone 20–30 sites, bladder floor
Nocturia (Δ%)
Daytime frequency (Δ%)
Injection sites and volume
3
3
1
3
3
2
2
3
3
3
3
3
LoE
Repeat injection had a better long-term success rate
Pdet and Qmax not decrease SF-36 & HAM-A ↑*
Pdet & Qmax ↓*
Botox better then BCG
Pdet &Qmax↓* Relapse at 5 months
KHS core↑27%/34%*
Pdet & Qmax ↓*
Others
J-F JHANG ET AL.
© 2014 The Japanese Urological Association
Botulinum toxin on interstitial cystitis
because of lack of efficacy or adverse events. The mean of ICSI, ICPI, total scores, VAS, functional bladder capacity and daytime frequency all showed significant improvement after BoNT-A treatment. The progressive improvement was also noted after repeat injection. Significantly better success rates were noted in patients who received four repeated injections (P = 0.024) and three injections (P = 0.05), compared with those who received a single injection. The results of these studies showed that repeat injections of BoNT-A could provide better therapeutic result sand long-term success rates than a single injection. We suggested the anti-inflammatory effect of repeat BoNT-A injection could reduce bladder inflammation in BPS/IC, and it results in a better therapeutic effect.
Ulcer type BPS/IC and BoNT-A injection BPS/IC is usually classified into ulcer (classic) and non-ulcer types based on cystoscopic findings.59 The ESSIC propose that Hunner’s “ulcer” is not a typical chronic ulcer, but rather a distinctive inflammatory lesion presenting a characteristic deep rupture through the mucosa. The term, “Hunner’s ulcer”, should be replaced by “Hunner’s lesion”; patients with Hunner’s lesion should be classified into ESSIC type 3.60 Some investigators asserted that patients with Hunner’s lesion have a tendency to be older, and have smaller bladder capacity and more urinary frequency than patients without the ulcer.61,62 A study of Peters et al. found that ulcerative type IC was associated with more severe lower urinary tract symptoms and less coexisting illnesses. He proposed that ulcerative and nonulcerative IC are two distinct diseases.63 In clinical experience, patients with BPS/IC and bladder ulceration often suffer from intractable lower abdominal pain, and the pain usually does not respond to medical treatment. The AUA guideline recommended the fulguration (with laser or electrocautery) and/or injection of triamcinolone if Hunner’s lesions are present.1 We recruited 10 patients with ESSIC type 3C and 30 patients with non-ulcer type BPS/IC to receive intravesical BoNT-A injections (100 U in 40 suburothelial injections) every 6 months.64 After four sets of BoNT-A injections, all 10 patients with ESSIC type 3C had global response assessment scores
International Journal of Urology (2014) 21 (Suppl 1), 49–55
doi: 10.1111/iju.12317
Review Article Potential therapeutic effect of intravesical botulinum toxin type A on bladder pain syndrome/interstitial cystitis Jia-Fong Jhang, Yuan-Hong Jiang and Hann-Chorng Kuo Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan
Abbreviations & Acronyms ATP = adenosine triphosphate AUA = American Urological Association BCG = bacillus Calmette–Guérin BoNT-A = botulinum toxin type A BPS/IC = bladder pain syndrome/interstitial cystitis CPSI-F = Chronic Prostatitis Symptom Index (female modification) ESSIC = European Society for the Study of Interstitial Cystitis FD vol = first desire to void volume HAM-A = Hamilton Anxiety Rating Scale HRQL = health-related quality of life ICPI = Interstitial Cystitis problem index ICSI = Interstitial Cystitis Symptom Index KHQ = King’s Health Questionnaire LOE = level of evidence MCC = maximum cystometric capacity NGF = nerve growth factor Pdet = maximal detrusor pressure Qmax = maximal urinary flow rate SF-36 = 36-item Medical Outcomes Study Short Form VAS = visual analog scale Correspondence: Hann-Chorng Kuo M.D., Department of Urology, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan. Email: [email protected]; [email protected] Received 17 July 2013; accepted 14 August 2013.
© 2014 The Japanese Urological Association
Abstract: Bladder pain syndrome/interstitial cystitis is characterized by bladder pain associated with urgency, frequency, nocturia, dysuria and sterile urine. Recent studies have shown that these bladder dysfunctions could originate from chronic inflammation or urothelial insult and proceed to a cascade of tissue reactions, which finally ascends to the central nervous system. Pilot studies of intravesical injection of botulinum toxin type A for bladder pain syndrome/interstitial cystitis had been introduced since 2005 with a promising result. Recent evidence suggests that botulinum toxin type A could significantly improve symptoms such as daytime frequency, nocturia, pain, quality of life and bladder capacity in bladder pain syndrome/interstitial cystitis patients. Single injection of botulinum toxin could not achieve long-term successful therapeutic result, and repeat injections could provide a better long-term success rate. However, patients with ulcer type bladder pain syndrome/ interstitial cystitis might not gain a benefit from botulinum toxin type A injection. Laboratory evidence showed that botulinum toxin type A for bladder pain syndrome/interstitial cystitis injection could induce peripheral desensitization, reduces bladder chronic inflammation and decreases apoptotic signal molecules in the urothelium. The present article reviewed the recent advances of botulinum toxin type A on bladder pain syndrome/ interstitial cystitis. Key word: bladder pain syndrome, botulinum toxin, interstitial cystitis.
Introduction BPS/IC is a syndrome of mystery in urology, and the pathophysiology of BPS/IC has not been fully understood. The clinical characteristic of BPS/IC is severe bladder pain associated with urgency, frequency, nocturia, dysuria and sterile urine. The diagnosis of IC/BPS is based on the symptoms and clinical urological findings, including characteristic cystoscopic features after hydrodistention under anesthesia.1 The National Institute of Diabetes and Digestive and Kidney Diseases criteria have been used to select more uniform patients for clinical research,2 and is today widely used in Asia for the diagnosis of IC.3 O’Leary proposed the ICSI and ICPI to measure lower urinary tract symptoms and their impact in 1997, and it is widely used in many studies now.4 Although many pathogeneses of IC/BPS have been proposed, the actual etiology remains unclear.5 The possible etiologies of IC/BPS include neurogenic inflammation, postinfection autoimmune process, mast-cell l activation and urothelial dysfunction.5–8 As the pathogenesis of BPS/IC remains unclear, the current goals of treatment are largely based on symptomatic relief. Cystoscopy with hydrodistention and biopsy is the first choice for diagnosis, classification and treatment. In a prospective study including 33 patients that underwent hydrodistention, the median symptom score for patients decreased after distention, but just 12 patients (36%) had at least 30% symptom improvement.9 Oral pentosan polysulfate sodium, hydroxyzine, amitriptyline, prednisone, cyclosporin, intravesical hyaluronic acid and heparin were carried out to treat BPS/IC, but the therapeutic result was controversial.10 Currently, BPS/IC does not have standard treatment.11 BoNT is one of the most powerful neurotoxins that inhibits the release of neurotransmitters from nerve fibers and the urothelium.12,13 It is widely used for medical purposes. The application of BoNT-A for the treatment of lower urinary tract symptoms was initiated in the late 1980s. Dykstra et al. described injections of BoNT-A into the external urethral sphincter in spinal cord injury patients to induce chemical sphincterotomy and treat detrusor sphincter dyssynergia.14 Intravesical BoNT-A injection has been used in patients with BPS/IC since 2004. The study reported that nine (69%) of 13 patients noted subjective improvement after BoNT-A treatment, and the symptoms score improved by 71%.15 Recently, many studies have discussed intravesical BoNT-A in BPS/IC, and it seems to have a promising result. We reviewed the possible patho49
J-F JHANG ET AL.
genesis of BPS/IC, and discussed the therapeutic mechanism, results, and adverse effects of intravesical BoNT-A injection in the present article.
Possible pathogenesis of BPS/IC The possible pathogenesis of BPS/IC had been widely discussed in the past 100 years. The most prevalent histology findings of bladder biopsy specimens in BPS/IC are denuded epithelium, mucosal ulceration, submucosa granulation tissue, and inflammatory and perineural infiltrate.16 These findings suggest an inflammatory process in the bladder, but the actual pathophysiology is still unknown. Recent studies have suggested that several pathophysiological mechanisms, including epithelial dysfunction, activation of mast cells, cell apoptosis, are involved in BPS/IC.17,18 The hypothesis of neuroimmune inflammation mediating the pathophysiology of BPS/IC has recently triggered heated discussion. An increase of the submucosal nerve fiber proliferation was found in BPS/IC bladder tissue, but it was not found in patients with bacterial or lupus cystitis.19 Lundeberg et al. also found increased mast cell count, histamine and nerve fibers in patients with BPS/IC. There was a good correlation between the number of nerve fibers and number of mast cells, as well as between the number of nerve fibers and the amount of histamine.20 Some substances released from neurons have been shown to induce mast cell secretion, and the mast cell–nerve interaction is well identified in human intestinal nociception.21 Substance P, a neuropeptide associated with inflammatory processes and pain, is thought to mediate mast cell accumulation, activation and degranulation. It could result in nociceptive sensitization.22 Substance P-containing nerve fibers were present in the bladder submucosa tissue of patients with BPS/ IC.23 That study suggested that a neuron-mediated inflammation process might be implicated in the pathophysiology of pain in BPS/IC, and has been shown to trigger mast cell secretion. Recent evidence also showed that urothelium apoptosis plays an important role in the pathogenesis of BPS/IC. By electron microscopy, an increased number of apoptotic urothelium with morphological changes of nuclear fragmentation in the bladder of BPS/IC had been identified.24 The percentage of Annexin V binding, an early apoptosis marker, was also significantly higher in bladder endothelial cells from BPS/IC patients with pain than control patients (P < 0.01). Our previous study investigated cell proliferation and apoptosis in the BPS/IC bladder.25 The ratio of ki-67-positive cells (to assess cell proliferation) was significantly downregulated, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining significantly increased in the bladder tissue of BPS/IC patients. Our further study suggested bladder inflammation could directly modulate the signaling pathway and increased urothelial cell apoptosis in BPS/IC. Protein antibody array and western blotting study showed that pro-apoptotic proteins including Bax, Bad, cleaved caspase-3 and phospho-p53 level were greater than those for the controls.18 Immunofluorescence staining of phospho-p38 were also positive in the urothelium of the patients with BPS/IC. Our evidence suggested abnormal and aggressive apoptosis might participate in the pathophysiology of BPS/IC. Neural upregulation might also participate in the pathophysiology of BPS/IC. Mechanoreceptors and chemoreceptors in the 50
bladder could trigger myelinated A-δ fibers or C-fibers in the smooth muscle or the submucosa in response to bladder distention.26 It is postulated that distention of the bladder causes release of ATP from epithelial cells. Released ATP can activate ligand-gated ion channels P2X3 receptors (purinoceptors) on nerve terminals in bladder urothelium or muscle, and evoke a neural discharge.27,28 Previous immunochemical evidence showed significant upregulation of the P2X3 receptor in BPS/IC bladder urothelial cells than normal controls.29 In cyclophosphamide-induced cystitis rat, a significant increase in the expression of substance P and calcitonin gene-related peptide was found in the L6-S1 spinal segment and dorsal root ganglia.30 No changes were observed in the L4-L5 spinal segment or dirsal root ganglion. Bladder pain also can be induced by activation of capsaicin-sensitive, unmyelinated afferent nerves.31,32 The transient receptor potential cation channel subfamily V member 1 (TRPV1) is the receptor of capsacin, and the increased mRNA expression of TRPV1 was found in bladder tissue of interstitial cystitis.33,34 In a cat animal model, dorsal root ganglion neurons (L4-S3) in the cat with BPS/IC showed increased neuron number and exhibited capsacin responses, which are increased in amplitude and desensitize slowly.35 This study suggested bladder inflammation could result in alterations in the neuropeptide expression in the central nerve system. Increasing excitability and sensitization of bladder afferent nerves could contribute to an increasing abnormal pain sensation with bladder distention.26 Although it is still unclear whether neural mechanisms and inflammation are the cause of BPS/IC, it is evident that neural upregulation plays a role in pain, urgency and frequency. Therapy for BPS/IC should act to regulate neural reaction, improve abnormal urothelial apoptosis and control inflammation.
Biology and mechanism of botulinum toxin BoNT is a protein and neurotoxin produced by the bacterium, Clostridium botulinum, and it was identified more than 100 years age.36 It has a 50-kd light chain and a 100-kd heavy chain, and seven immunologically distinct neurotoxins (types A to G) are produced by different C. botulinum strains. In culture fluid and food with acidic conditions, the botulinum neurotoxins associate with non-toxic components, and form large complexes designated as progenitor toxins. The progenitor toxins are found in three forms: 19S, 16S and 12S, and they are composed of neurotoxin, hemagglutinin and non-toxic nonhemagglutinin.37,38 The neurotoxin of BoNT is initially biologically inactive until it is activated by proteolytic cleavage into a 100-kDa heavy chain and a 50-kDa light chain.39 BoNT-A progenitor toxins have been used for treating patients with strabismus, blepharospasm and nystagmus.40 It has been marketed as Botox (onabotulinumtoxinA) in the USA (Allergan, Irvine, CA, USA) and as Dysport (abobotulinumtoxininA) the UK (Ipsen, Slough, Berkshire, UK). BoNT recognizes and enters neurons by binding to the synaptic vesicle protein, SV2, during neurotransmitter exocytosis when more active receptors are exposed.41 Through endocytosis of this toxin, the disulphide bond is cleaved. The light chain is the true active moiety of the molecule, and can combine with SNAP-25 protein to inhibit exocytosis of the acetylcholine © 2014 The Japanese Urological Association
Botulinum toxin on interstitial cystitis
from the vesicles. The affected neuromuscular junctions become paralyzed after injection of BoNT.42 Although BoNT is known to show cholinergic specificity, release of other transmitters can be inhibited. Smith et al. found that intravesical injection of BoNT-A could inhibit ATP release from the urothelium on bladder contraction.43 In a chronic spinal cord injury rat model, BoNT-A injection also could normalize ATP and nitric oxide release from urothelium.44 Recent studies in rats showed that BoNT-A inhibited sensory neuropeptide release, including substance P and calcitonin gene-related peptide, from isolated rat bladder preparations after cyclophosphamide-induced inflammation, suggesting that BoNT-A had a potential clinical benefit in the treatment of neurogenic inflammation.45 BoNT-A injection in surgical wounds on a rat resulted in less infiltration of inflammatory cells than the control group at the second week, and there was a lower transforming growth factor beta1 expression in the BoNT-A group.46 This result suggested that BoNT injection might control local tissue inflammation.
Intravesical BoNT-A in BPS/IC Pilot studies reporting the efficacy of BoNT-A for treating BPS/IC since 2004 have shown controversial results. Smith et al. reported 13 female patients with BPS/IC received BoNT-A 100–200 U into 20–30 sites submucosally in the trigone and floor of the bladder with hydrodistention at the same time.15 The ICSI and ICPI mean scores in these patients improved by 71% and 69%, respectively (P < 0.05). Daytime frequency, nocturia and pain by visual analog scale also decreased by 44%, 45%, and 79%, respectively (P < 0.01). The onset of symptom relief was 5–7 days after treatment, and the mean duration of symptom relief was 3.7 months. Our preliminary study of BoNT-A in BPS/IC was carried out in 2005, and 10 patients with BPS/IC who had failed conventional treatments were enrolled in this study.47 In 10 patients, 100 U of BoNT-A was suburothelially injected into 20 sites, and an additional 100 U was injected into the trigone of 5 of these patients. Just two patients’ bladder pain and urinary frequency were improved at 3 months after treatment, and the five patients that received trigonal injection had no therapeutic effect on symptoms or urodynamic improvement. Giannantoni et al. reported her series of BPS/IC patients who received BoNT-A injection and were followed since 2006.48 In that study, 200 U of BoNT-A was injected submucosally in the trigone and bladder floor under. Approximately 80% of patients reported a subjective improvement at 1 month after therapy. Mean VAS scores, and mean daytime and night-time urinary frequency decreased significantly compared with pretreatment. The most recent studies support the promising therapeutic effects of BoNT-A in patients with BPS/IC. Ramsay et al. carried out a prospective study of 11 patients with BPS/IC that received 200–300 U BoNT-A, and found it could improve symptoms scores by 20% in 14 weeks after treatment.49 Giannantoni et al. reported her 1-year follow-up report of BoNT-A injection in BPS/IC; patients showed significant improvement of VAS scores and frequency at 1-month and 3-month follow up.50 Giannantoni et al. also used the HAM-A and the SF-36 to evaluate psychological function and quality of life in 14 BPS/IC patients who received BoNT-A injection. At the 3-month follow up, patients showed significant improvement of anxiety, depres© 2014 The Japanese Urological Association
sion and quality of life.51 We designed a prospective and randomized control study in 67 patients with refractory BPS/ IC.52 A total of 44 patients received suburothelial BoNT-A injection with 200 U or 100 U in 2 weeks after cystoscopic hydrodistention, and 23 patients received cystoscopic hydrodistention alone. At 3 months after treatment, the improvement of the VAS score, and functional and cystometric bladder capacity increases were significant only in the BoNT-A groups. A successful therapeutic result at 6, 12 and 24 months was reported in 31 (71%), 24 (55%) and 13 (30%) patients in the BoNT-A groups, respectively. The successful therapeutic result rate in BoNT-A groups at 12 and 24 months was significantly better than it in the cystoscopic hydrodistention group. BCG instillation therapy for BPS/IC was also compared with BoNT-A injection.53 The improvement of pelvic pain, frequency urgency and nocturia in the BoNT-A injection group was significantly better than it in the BCG instillation group. Our recent prospective study that enrolled 67 patients is currently the largest series of BoNT-A single injection in refractory BPS/IC.54 The patients received 100 U BoNT-A suburothelial injection to 40 sites with cystoscopic hydrodistention, and were followed every 3 months. The ICSI, ICPI, O’Leary–Sant Score, VAS, frequency, nocturia, functional bladder capacity, cystometric bladder capacity and global response assessment were significantly improved in the patients at 3-month and 6-month follow up. We suggested 100 U BoNT-A intravesical single injection is effective in relief of bladder pain and lower urinary tract symptoms at short-term follow up. The results of clinical studies for the use of BoNT-A in BPS/IC are listed in Table 1.
Repeat BoNT-A injections Although BoNT-A injection provides symptomatic relief in treating BPS/IC, long-term therapeutic effects have not been achieved after single injections. Giannantoni et al. reported that 11 of 15 patients with BPS/IC who had received BoNT-A injection had bladder pain recurrence at 5 months after treatment. Bladder pain had recurred in all cases at 1-year follow up.50 In our series, patients who received a single BoNT-A injection with cystoscopic hydrodistention had just 55% and 30% successful therapeutic results at 12- and 24-month follow up, respectively.52 Giannantoni et al. reported 13 women with BPS/IC who received repeat BoNT-A 200 U injection with a mean of 4.8 ± 0.8 injections per patient.55 The mean interval between two consecutive injections was 5.25 ± 0.75 months. The mean VAS scores, and mean daytime and night-time urinary frequency had persistently significantly decreased compared with pretreatment at 1-month, 4-month, 5-months, 1-year and 2-year follow up. The maximum cystometric capacity also had a persistently significant improvement. We also carried out a study to investigate the clinical efficacy of repeat BoNT-A injections.58 A total of 81 patients with refractory BPS/IC received suburothelial injection of BoNT-A 100 U to 40 sites. Repeat BoNT-A therapy was recommended at 6 months after the initial treatment if patients felt a relapse of baseline symptoms or desired repeated treatment to achieve a better treatment outcome. The procedure was repeated every 6 months up to four times, or until patients declared their symptoms had significantly resolved or patients did not want repeated treatment 51
52
13
10
14
11
15
15 29 23 16 16 13
26
14
20
67
81 30
Smith et al. 200415
Kuo, 200547
Giannantoni et al. 200648
Ramsay et al. 200749
Giannantoni et al. 200850
Kuo and Chancellor 200952
Pinto et al. 201056
Giannantoni et al. 201051
Gottsch et al. 201157
Chung et al. 201254
Kuo, 201358
24 mo
6 mo
3 mo
3 mo
3 mo
22 wks 23 wks 24 mo
3 mo
3 mo
14 wks
3 mo
3 mo
3 mo
Follow up
100 U, 20 mL, 1 injection 100 U, 20 mL, 4 injections
100 U, 20 mL
50 U, 2 mL, Botox Placebo, saline 2 mL
200 U, 20 mL, Botox
200 U 20 mL Botox + HD 100 U 20 mL Botox + HD HD BCG 300 U Botox Repeat mean 4.8 times injections/patient 200 U, 20 mL, Botox 100 U, 10 mL, Botox
200–300 U, 20–30 mL, Botox 200 U, 20 mL, Botox
100–200 U, 10–20 mL, Botox or Dysport 100–200 U, 10–20 mL, Botox 200 U, 20 mL, Botox
BoNT-A preparation (dose)
Δ%: change from baseline, percentage. *Significant improvement for baseline.
Giannantoni et al. 201055
El-Bahnasy et al. 200953
n
Clinical studies for the use of BoNT-A in BPS/IC
Authors, year
Table 1
– −47%* – −56%* −51% −24% −5% –54%* –100%* −58.4%*
−62%* −74%*
−25%* −35%* −33% −43%* −34%* −25% −14% −31% −68%* −51%*
−59%*
20 sites, bladder floor and −56%* trigone 2 sites, periurethral injection at 3 & 9 o’clock, in the region of the bladder neck, 40 sites, bladder floor −31%* except trigone 40 sites, bladder floor −23%* except trigone −21%*
10 sites, trigone only
– – 20 sites, bladder floor and trigone
20 sites, bladder floor and trigone 40 sites, bladder floor except trigone
63%*
90%*
163%*
–
62%* 26%* 4%
38%*
29%
30%*
27%*
57%*
MCC (Δ%)
−46%*
−71%*
−55%* −39%* −18% −81%* −96%* −39.1%*
−28%*
–
−34%*
−25%*
−79%*
VAS (Δ%)
40%* 17% 9%
27%*
77%*
–
144%*
–
–
50%*
58%*
FD vol (Δ%)
–
−66, −56%*
−42, −36%* −38, −35%* −23, −23%* –
–
–
–
–
−69, −71%*
ICPI, ICSI (Δ%)
−28% −16%
12%* 18%*
−30%* −37%*
26%* 65%*
−28, −27%*
No significant inter-or intragroup improvements in CPSI-F, AUA Symptom Index, Graded Chronic Pain Scale, Perceived Stress Scale and VAS −36%* 8% −37%* 32%* −38, −34%*
−45%*
−44%*
20–30 sites, trigone and bladder floor 20–30 sites, Bladder floor only or with trigone 20 sites, bladder floor and trigone 20–30 sites, bladder floor
Nocturia (Δ%)
Daytime frequency (Δ%)
Injection sites and volume
3
3
1
3
3
2
2
3
3
3
3
3
LoE
Repeat injection had a better long-term success rate
Pdet and Qmax not decrease SF-36 & HAM-A ↑*
Pdet & Qmax ↓*
Botox better then BCG
Pdet &Qmax↓* Relapse at 5 months
KHS core↑27%/34%*
Pdet & Qmax ↓*
Others
J-F JHANG ET AL.
© 2014 The Japanese Urological Association
Botulinum toxin on interstitial cystitis
because of lack of efficacy or adverse events. The mean of ICSI, ICPI, total scores, VAS, functional bladder capacity and daytime frequency all showed significant improvement after BoNT-A treatment. The progressive improvement was also noted after repeat injection. Significantly better success rates were noted in patients who received four repeated injections (P = 0.024) and three injections (P = 0.05), compared with those who received a single injection. The results of these studies showed that repeat injections of BoNT-A could provide better therapeutic result sand long-term success rates than a single injection. We suggested the anti-inflammatory effect of repeat BoNT-A injection could reduce bladder inflammation in BPS/IC, and it results in a better therapeutic effect.
Ulcer type BPS/IC and BoNT-A injection BPS/IC is usually classified into ulcer (classic) and non-ulcer types based on cystoscopic findings.59 The ESSIC propose that Hunner’s “ulcer” is not a typical chronic ulcer, but rather a distinctive inflammatory lesion presenting a characteristic deep rupture through the mucosa. The term, “Hunner’s ulcer”, should be replaced by “Hunner’s lesion”; patients with Hunner’s lesion should be classified into ESSIC type 3.60 Some investigators asserted that patients with Hunner’s lesion have a tendency to be older, and have smaller bladder capacity and more urinary frequency than patients without the ulcer.61,62 A study of Peters et al. found that ulcerative type IC was associated with more severe lower urinary tract symptoms and less coexisting illnesses. He proposed that ulcerative and nonulcerative IC are two distinct diseases.63 In clinical experience, patients with BPS/IC and bladder ulceration often suffer from intractable lower abdominal pain, and the pain usually does not respond to medical treatment. The AUA guideline recommended the fulguration (with laser or electrocautery) and/or injection of triamcinolone if Hunner’s lesions are present.1 We recruited 10 patients with ESSIC type 3C and 30 patients with non-ulcer type BPS/IC to receive intravesical BoNT-A injections (100 U in 40 suburothelial injections) every 6 months.64 After four sets of BoNT-A injections, all 10 patients with ESSIC type 3C had global response assessment scores
