|Ahead of print publication
Will repeated botulinum toxin A improve detrusor overactivity and bladder compliance in patients with chronic spinal cord injury?
Sheng-Fu Chen, Hann-Chorng Kuo
Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
|Date of Submission||15-Apr-2020|
|Date of Acceptance||30-Apr-2020|
|Date of Web Publication||29-Jul-2020|
Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 707, Section 3, Chung-Yang Road, Hualien
Source of Support: None, Conflict of Interest: None
Chronic spinal cord injury (SCI) can induce neurogenic detrusor overactivity (NDO), leading to urinary incontinence and renal damage due to low bladder compliance and high detrusor pressure during the storage and voiding of urine. In 2011, Botox® (onabotulinumtoxinA, botulinum neurotoxin serotype A [BoNT-A]) was approved by the Food and Drug Administration for the treatment of NDO. Intradetrusor injection of BoNT-A has been shown to have clinical utility for the treatment of urinary incontinence, with consequent improvements in quality of life for patients. In the past 20 years, this treatment has been shown to be an effective treatment for patients with SCI refractory to antimuscarinic medication. The present review focused on publications in MEDLINE/PubMed relating to botulinum toxin to evaluate the treatment outcomes of repeated injection of BoNT-A, the mechanisms of action, results of clinical and urodynamic studies, and adverse effects.
Keywords: Bladder compliance, Botulinum toxin A, Detrusor overactivity, Spinal cord injury
|How to cite this URL:|
Chen SF, Kuo HC. Will repeated botulinum toxin A improve detrusor overactivity and bladder compliance in patients with chronic spinal cord injury?. Tzu Chi Med J [Epub ahead of print] [cited 2021 Mar 3]. Available from: https://www.tcmjmed.com/preprintarticle.asp?id=291102
| Introduction|| |
A worldwide investigation revealed the incidence of spinal cord injury (SCI) to be 12.1-57.8 per million, representing a significant cause of morbidity and mortality in most developing countries. In patients with chronic SCI, there are two major problems which can occur due to neurogenic lower urinary tract dysfunction (NLUTD): (1) failure to store urine due to detrusor overactivity (DO) or urethral incompetence and (2) failure to empty the bladder due to detrusor areflexia, bladder neck dysfunction, or detrusor sphincter dyssynergia (DSD). Most patients usually exhibit complications, experiencing problems with both storage and emptying of the bladder, which results in poor quality of life (QoL). More seriously, high intravesical pressure may damage the upper urinary tract, which can cause renal scarring and chronic renal insufficiency if it is not well managed. In the case of SCI, high intravesical pressure is a result of poor bladder compliance during the storage phase and DO with DSD in voiding phase. Several studies had shown good therapeutic efficacy of onabotulinumtoxinA (botulinum neurotoxin serotype A [BoNT-A]) intradetrusor injection in SCI patients to inhibit DO which improving incontinence and QoL,. However, to maintain large bladder compliance is also very important because low bladder compliance would lead to high bladder pressure with little urine volume during the storage which increased renal loading. Therefore, the aim of this study is to search the long-term outcome of improving DO and bladder compliance by repeated botulinum toxin A injection.
Bladder compliance is described by a mathematical expression of the volume of urine required to produce a unit rise in pressure, which is measured during cystometric filling. This parameter indicates how the bladder wall will react to stretching. The value of bladder compliance in urodynamic study is calculated by the infusion volume divided by elevated pressure in the storage phase, which is △V/△P. According to the guidelines of the European Association of Urology, the primary goal of treatment for NLUTD is protecting renal function and preventing urinary tract infection. The goal of treatment is to decrease the detrusor leak point pressure to <40 cmH2O in the storage phase. Over the last two decades, several studies have demonstrated that injection of onabotulinumtoxinA (BoNT-A) into the detrusor can have therapeutic benefits to patients with SCI in terms of neurogenic DO (NDO) and QoL,,,. Our previous studies have demonstrated that the repeated BoNT-A injections can improve urodynamic parameters, renal function, and bladder urothelium dysfunction,,,. The present article aims to provide a state-of-the-art review of the utility of botulinum toxin A in the case of chronic SCI with NDO and poor bladder compliance.
This review study searched relevant articles from 2000 to 2019 using MEDLINE/PubMed. The keywords included spinal cord injury, neurogenic detrusor overactivity, bladder compliance, botulinum toxin, Botox, and BTX-A, repeated injection. All papers identified were English language, full-text papers. References of retrieved articles were also hand-searched to find additional articles that may have been missed in the database search. All trials were checked the use of repeated BoNT-A injections into the detrusor for the treatment for NDO after SCI. Treatment outcomes such as urodynamic reports, urinary incontinence improvement, and adverse events were all included for discussing.
| How Does Spinal Cord Injury Cause Low Urinary Tract Dysfunction?|| |
Although the underlying pathophysiology of DO and altered compliance induced by chronic SCI were well studied, the mechanisms are not fully understood. In healthy individuals, the bladder afferent pathways consist of small, myelinated A-delta and unmyelinated C-fibers. The A-delta fibers primarily transmit signals from mechanoreceptors which detect bladder fullness or wall tension, while the C-fibers transmit noxious signals and initiate painful sensations. In patients with SCI, the reflex connections of the spinal cord appear to undergo considerable reorganization following interruption of the descending pathways from the brain. As a result of this aberrant neural input, such patients commonly experience extensive fibroproliferative remodeling of the bladder, resulting in diminished functional capacity and DO, with consequent poor bladder compliance. Elevated bladder pressure during the storage phase due to either low bladder compliance or DO is the major cause of renal deterioration
In 1990, de Groat et al. demonstrated that the C-fibers compensate as the afferent limb of the voiding reflex in a rat model of SCI. Besides, rapid disruption of the uroepithelial barrier in SCI bladder, which manifests as loss of cell-cell interactions, decreased transepithelial resistance and increased water and urea permeability. The bladders of patients with SCI exhibit decreased expression of urothelial adhesion protein E-cadherin and junction protein zonula occludens-1, while suburothelial inflammation and urothelial cell apoptosis are increased. These molecular features suggest that urothelial dysfunction, increased suburothelial inflammation, and apoptosis coexist in patients with chronic SCI. Together, these factors might also alter the expression of sensory molecules including purinergic receptor P2X ligand-gated ion channel 3 (P2X3), transient receptor potential vanilloid receptor subfamily 1, adenosine triphosphate, and nitric oxide (NO). Urothelial dysfunction may also lead to increased excitability of C-fibers, which then become the predominant afferent nerves involved in regulation of the micturition reflex after SCI. Changes in the bladder reflex pathway may result in NDO and urinary incontinence after SCI.
The observed neuroplasticity of bladder afferents after SCI might be attributable to urothelial dysfunction or changes in the expression of urothelial sensory proteins. Proteins including M2, M3, and endothelial NO synthase have been shown to be significantly downregulated in bladder urothelium samples of patients with SCI compared with healthy individuals, demonstrating the influence of sensory proteins on the pathophysiology of NDO. Disruption of the urothelial barrier initiates a cascade of bladder dysfunction events, eventually resulting in suburothelial inflammation and vulnerability to chronic or recurrent cystitis and/or bacterial infection. Suburothelial inflammation might also affect urothelial function, leading to a perpetuating cycle.
| The Evolution of Botulinum Toxin Type a in Treatment of Neurogenic Detrusor Overactivity|| |
In the 20th century, anticholinergics were the standard first-line treatment for NDO in patients with chronic SCI. However, many patients are unable to tolerate the side effects long-term treatment with these drugs, which include dry mouth, visual disturbance, and constipation. Intravesical therapy became popular in the 1990s, with the instillation of vanilloid compounds such as capsaicin and resiniferatoxin becoming the subject of much research into the treatment of neurogenic and non-NDO. Capsaicin acts selectively on unmyelinated C-fibers, which are thought to become predominant in reflex contractions of the bladder after SCI,. Resiniferatoxin is an ultrapotent analog of capsaicin which induces similar desensitization effects as capsaicin with less undesirable effects,. However, although resiniferatoxin exhibits superior efficacy, the duration is not consistent.
In 2000, Schurch et al. published the first report on the injection of botulinum toxin type A (Botox, Allergan® 200/300 units) into the detrusor muscle of patients with SCI for the treatment of NDO. The authors reported the induced bladder paresis to persist for at least 9 months. In 2005, Schurch reported the results of the first randomized, placebo-controlled study of injection of BoNT-A into the detrusor, which demonstrated the rapid, well-tolerated, clinically significant decrease in urinary incontinence in response to the drug. Another type of botulinum toxin type A (Dysport®, Ipsen Biopharm, Slough, UK) is also currently used for the treatment of NDO, with the administration of around 750-1000 U by injection into the detrusor reported to be effective,. A review of the use of neurotoxins for the treatment of urinary incontinence in patients with SCI concluded that BoNT-A therapy required fewer treatments with longer intervals between treatments than resiniferatoxin. Compared with traditional therapy, injection of BoNT-A injection is significantly more efficacious than oral oxybutynin in terms of the improvement in urinary continence, urodynamic parameters, and QoL. In the last two decades, several open-label studies have revealed that detrusor injection of 200 or 300 U of BoNT-A can improve clinical and urodynamic parameters and QoL in patients with refractory NDO following SCI,,,,.
In 2011, Botox® (onabotulinumtoxinA) was approved by the USA Food and Drug Administration for the treatment of NDO associated with conditions such as SCI and multiple sclerosis. The dose of BoNT-A for such treatment was controversial until recent global, phase III, multicenter trials revealed that administration of either 200 or 300 U of BoNT-A caused a significant reduction in urinary incontinence and improved urodynamic parameters and QoL of patients with NDO. No clinically relevant differences were observed in terms of efficacy or duration of effect between the two doses. However, the 200-U dosage was associated with fewer adverse effects,. After BoNT-A treatment, the subjective primary outcome of “dryness” was achieved in 62.9% of patients receiving 200 U of BoNT-A and 61.6% of those receiving 300 U. Therefore, recent consensus for the ideal dose is 200 U for the treatment of NDO. A recent systemic meta-analysis including 17 studies and 1455 patients with SCI demonstrated BoNT-A to be effective in increasing maximum cystometric capacity, volume at first involuntary detrusor contraction, cystometric bladder capacity (all P < 0.00001), bladder compliance (P = 0.001), and complete dryness (P = 0.0003) and in decreasing detrusor pressure (Pdet) and the incidence of DO (both P < 0.00001). Several reports have shown combined detrusor and urethral injection to decrease detrusor leak-point pressure in the case of DSD,,,.
With regard to adverse effects of BoNT-A, patients should be made aware of the risks of high post-void residual volume or retention with the potential requirement of self-catheterization, mild hematuria, and urinary tract infection. Other rare (<5%) side effects include nausea, vomitus and flu-like symptoms, depression, muscle spasm, constipation, muscle weakness, insomnia, dizziness, diarrhea, and de novo autonomic dysreflexia. Wyndaele and Van Dromme reported distant muscular weakness to be a side effect of administration of 300 U Botox or 1000 U Dysport.
| Pathophysiology and Mechanism of Botulinum Toxin Type a in the Treatment of Neurogenic Detrusor Overactivity and Bladder Compliance|| |
Botulinum toxin was first described by van Ermengem in 1897, which was extracted from the bacterium Clostridium botulinum. The toxin mediates proteolytic cleavage of protein subunits of soluble N-methylmaleimide-sensitive attachment protein receptor (SNARE) proteins in the synaptic terminal. There are seven BoNT serotypes (A-G); each serotype specifically and noncompetitively cleaves one site of one member of the SNARE protein family: BoNT-A cleaves synaptosomal-associated protein with a molecular weight of 25 kDa (SNAP-25); BoNT-C cleaves syntaxin; and serotypes B, F, and G cleave vesicle-associated membrane protein/synaptobrevin. The SNARE proteins play a ubiquitous role in vesicle-membrane fusion during neurotransmitter release in both the peripheral and central nervous systems; thus, BoNT-A blocks presynaptic neurotransmitter release by binding to gangliosides and interacting with synaptic vesicle protein 2, in order to cleave SNAP-25. As SNAP-25 is necessary for the fusion of synaptic vesicles at the cellular membrane, SNARE-mediated exocytosis of several neurotransmitters is therefore inhibited. Several studies have demonstrated that treatment of neuronal systems and cell cultures with BoNT-A inhibits the release of acetylcholine, substance P, glutamate, and calcitonin gene-related peptides,,,. Furthermore, botulinum toxin may also act on afferent pathways, particularly via subepithelial neuromediators. Patients with NDO have been demonstrated to have increased transient receptor potential cation channel subfamily V member 1 and purinergic receptor P2X3-immunoreactive suburothelial innervation. Another study has shown that BoNT-A inhibits the release of adenosine triphosphate from the urothelium. Bladder levels of neurotrophic growth factor have been reported to decrease significantly in patients with NDO who receive treatment with BoNT-A; the toxin appears to inhibit the release of norepinephrine to alpha- and beta3-adrenoreceptors, which are involved in bladder neck contraction and detrusor relaxation. Therefore, BoNT-A has a complex inhibitory effect on vesicular release of excitatory neurotransmitters as well as the axonal expression of other proteins in the urothelium or suburothelium. Above evidence indicated that BoNT-A inhibits both the sensory and motor arms of the micturition reflex which can reduce NDO.
Bladder compliance is determined by the viscoelastic properties of bladder components such as the smooth muscle, collagen, and elastin, and poor compliance is correlated with the presence of neurological conditions and degree of inflammation. Persistent inflammation including suburothelial inflammation leads to urothelium dysfunction. Several studies have presented evidence of the anti-inflammatory effects of BoNT-A injection. Using an animal model, Khera et al. showed that adenosine triphosphate (ATP) is significantly inhibited by intravesical instillation of BoNT-A in the bladders of rats with SCI. NO can be released from bladder urothelium in response to stretch. Smith et al. reported that abnormal levels of urothelial ATP and NO improved following BoNT-A treatment. Lucioni et al. reported BoNT-A injection to significantly inhibit the release of substance P and calcitonin gene-regulated peptide in the case of acute and chronic bladder inflammation in rats. In our previous study, we found that intradetrusor injection of BoNT-A improved urothelium dysfunction; urothelial barrier function recovered after BoNT-A injections due to improvements in the adhesive and tight-junction protein levels,. This result might, in part, explain the mechanism of BoNT-A through the anti-inflammatory effects which altered compliance.
| The Efficacy of Repeated Injection of Botulinum Toxin Type a|| |
A Phase III clinical trial revealed the median time to retreatment request to be greater following administration of 200 or 300 U of BoNT-A than placebo (256 and 254 days, respectively, vs. 92 days). Our previous study found the regained urinary continence or improved urgency of single detrusor injection of 200 U of BoNT-A to be 73.3% among patients with SCI and NDO, with therapeutic effects lasting 3-9 months (mean, 5.3 months).
Giannantoni et al. reported that 17 cases, during 6 years of follow-up after repeated injection of BoNT-A, experienced significant improvements in the first uninhibited detrusor contraction and maximum bladder capacity (P < 0.001 for both) and significantly decreased maximum pressure of contractions (P < 0.01). Fifteen (88.2%) patients were completely continent after treatment. Hori et al. reported that 67% SCI patients were still actively undergoing repeat BoNT-A injections, and among the 48 patients, 43 (90%) were satisfied with BoNT-A for long-term management of NDO. Pannek reported 27 patients underwent repeated BoNT-A treatments for a mean period of 7.1 years, the long-term success rate was 74%, and bladder compliance increased from 42.2 ± 38.4 to 73.1 ± 70.2 (mL/cmH2O). However, the therapeutic effects were insufficient in around one quarter of patients who required major surgical intervention. Our previous study reported that, among 30 patients who received four injections of 200 U of BoNT-A, the mean bladder capacity increased from 207 ± 111 to 412 ± 33 mL and the mean detrusor pressure decreased from 39.8 ± 21.7 to 20.6 ± 19.1cmH2O. All patients exhibited improvements in the grade of incontinence, but some patients did not show significant improvement in bladder compliance and thus required surgical intervention as the high detrusor pressure leads to impairment of renal function. We discovered that patients for whom bladder compliance increased by <10 cmH2O or Pdet decreased by <10cmH2O following treatment exhibited decreased glomerular filtration rate, and further aggressive treatment was needed.
In another study, we found that the therapeutic efficacy of BoNT-A decreased slightly after the fourth injection. The overall rate of satisfaction after repeated injections was 59.3%, and the failure rate was 33.9%. Of these, 16.9% reported no significant improvement and the remaining patients dropped out due to adverse events of urinary tract infection and autonomic dysreflexia. We also found that repeated 6 monthly detrusor injection of 200 or 300 U of onabotulinumtoxinA did not lead to significant improvements in urodynamic parameters, renal function, or severity of incontinence. Despite the clinical evidence of initial efficacy of BoNT-A (lasting around 24-36 weeks), we recommend that injections should be repeated every 24 weeks to maintain lower detrusor pressure. Other indicators of bladder urothelial dysfunction, such as the expression of adhesive and junction proteins in the bladders of patients with SCI, improved after three cycles of BoNT-A treatment.
Leitner et al. reported the results of a >15-year study, which revealed that around 60% of patients continued to receive intradetrusor injection of BoNT-A for NDO, which was associated with sustained improvements in urodynamic parameters. Bladder compliance increased from 36 ± 28 to 92 ± 64 (mL/cmH2O), andP(detmax) decreased from 46 ± 30 to 30 ± 26 cmH2O. DO rate decreased from 100% to 71%. However, 21% of the study population did not exhibit a clinical and/or urodynamic response and switched to other treatments. A Phase III, multicenter, 4-year trial of BoNT-A for NDO found that administration of 200 U of BoNT-A consistently reduced the number of episodes of urinary incontinence by 3.2-4.1 per day after six treatments, which was similar to 300 U. The most common adverse events were urinary tract infections, urinary retention, and de novo CIC, in which the occurrence rates were 29.5%, 3.4%, and 6.0% in 200 U, and 43.0%, 15.0%, and 4.8% in 300 U, respectively. However, this study did not report urodynamic findings, and so we cannot know the precise effects on bladder compliance. Koschorke et al. suggested that urinary continence alone is not sufficient to evaluate the treatment outcomes of detrusor injection of BoNT-A for NDO because high intravesical pressure may be missed in continent patients. In their study, 98 of the 148 patients (66%) with NDO incontinence were continent after BoNT-A treatment; however, 18 of these had a maximum Pdet of >40 cmH2O during the storage phase due to poor bladder compliance which may lead to renal function impairment. Therefore, the actual success rate might be overestimated.
In a study involving myelodysplastic children and patients with SCI and NDO with a median follow-up of 4.5 years, Akbar et al. found repeated BoNT-A treatments at least 3 treatment cycles to be effective, with no antibody formation or fibrosis of the detrusor muscle observed. The bladder compliance was 16.28 ± 14.01 before treatment and was 37.39 ± 20.12 after first injection and was sustained 38.95 ± 20.39 after the third treatment. Grosse et al. showed that, in terms of therapeutic outcomes, including subjective satisfaction and objective parameters, such as compliance and cystometric capacity, showed that repeated BoNT-A injections were just as effective as the first treatment. Stoehrer et al. reported a 7 years experiences of repeated detrusor injection of 300 U of Botox® or 750 U of Dysport for NDO were both effective, long-lasting, and repeatable. No significant differences were noted in outcomes between the two preparations. A recent study compared onabotulinumtoxinA with abobotulinumtoxinA for NDO showed that sustainable long-tern outcomes were achieved following both treatments. However, if the efficacy was not satisfactory, switching to another type of BoNT-A did not improve the response.
Another systematic review and meta-analysis of repeat BoNT-A injection for NDO showed that patients who received ≤4 injections reported stable improvements in QoL after the first and last injections, whereas patients who received ≥5 injections reported a significant decrease in QoL after the final injection. Male patients, underlying neurological disorder, and high maximum Pdet during storage prior to treatment appear to be risk factors for poor urodynamic outcomes. Our previous study showed lack of bladder compliance or Pdet improvement after BoNT-A injection lead bad outcomes. In patients with poor therapeutic effects of repeated BoNT-A treatment, which may cause frequent UTI and renal function impairment, advanced surgery such as augmentation enterocystoplasty or urinary diversion was needed. Based on the recent literature, repeated detrusor injection of BoNT-A appears to offer sustainable benefits for most patients with SCI and NDO, although a proportion of patients will experience a gradual decrease in efficacy. Most studies used “by patients request” protocol when patient subjective feels symptoms relapse. The median duration of clinical effects was 36 weeks, although some lasted shorter and some longer. However, our protocol of repeated injection is periodic 24-week injection rather than by patient request. We think the benefit of this is to maintain low intravesical pressure in storage phase which achieves the treatment goal. For patients with NDO, urinary continence is not sufficient alone as an outcome assessment of intradetrusor BoNT-A injection, as high intravesical pressures during storage might be missed in a significant proportion of continent patients. Therefore, we strongly recommend that urodynamic parameters should be assessed as a routine part of follow-up. [Table 1] summarizes the repeated intradetrusor BoNT-A injection in the current study.
|Table 1: Description of studies of repeated botulinum toxin for treat chronic spinal cord injury bladders|
Click here to view
| Conclusions|| |
Patients with chronic SCI and NDO can achieve long-term improvements in DO and bladder compliance through repeated injection of BoNT-A. However, there is evidence of decreasing efficacy over time for some patients. Urinary continence alone is not a sufficient evaluation of outcome, because some continent patients may have poor compliance and high detrusor pressure, which can cause renal damage. If bladder compliance increases by <10 cmH2O and Pdet decreases by <10cmH2O through treatment, treatment is considered to have failed. Annual assessment of urodynamic parameters should be considered an important aspect of the standard care for NLUTD.
Financial support and sponsorship
This study was supported by the grant of Buddhist Tzu Chi Medical Foundation (TCMF-SP 108-01).
Conflicts of interest
There are no conflicts of interest.
| References|| |
van den Berg ME, Castellote JM, Mahillo-Fernandez I, de Pedro-Cuesta J. Incidence of spinal cord injury worldwide: A systematic review. Neuroepidemiology 2010;34:184-92.
Kuo HC. Quality of life after active urological management of chronic spinal cord injury in Eastern Taiwan. Eur Urol 1998;34:37-46.
Patki PS, Hamid R, Arumugam K, Shah PJ, Craggs M. Botulinum toxin-type A in the treatment of drug-resistant neurogenic detrusor overactivity secondary to traumatic spinal cord injury. BJU Int 2006;98:77-82.
Reitz A, Stöhrer M, Kramer G, Del Popolo G, Chartier-Kastler E, Pannek J, et al. European experience of 200 cases treated with botulinum-A toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity. Eur Urol 2004;45:510-5.
Grosse J, Kramer G, Stöhrer M. Success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol 2005;47:653-9.
Wyndaele JJ, Gammie A, Bruschini H, De Wachter S, Fry CH, Jabr RI, et al. Bladder compliance what does it represent: Can we measure it, and is it clinically relevant? Neurourol Urodyn 2011;30:714-22.
Stöhrer M, Blok B, Castro-Diaz D, Chartier-Kastler E, Del Popolo G, Kramer G, et al. EAU guidelines on neurogenic lower urinary tract dysfunction. Eur Urol 2009;56:81-8.
Schurch B, Stöhrer M, Kramer G, Schmid DM, Gaul G, Hauri D. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: A new alternative to anticholinergic drugs? Preliminary results. J Urol 2000;164:692-7.
Karsenty G, Denys P, Amarenco G, De Seze M, Gamé X, Haab F, et al. Botulinum toxin A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity/neurogenic overactive bladder: A systematic literature review. Eur Urol 2008;53:275-87.
Ginsberg D, Gousse A, Keppenne V, Sievert KD, Thompson C, Lam W, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol 2012;187:2131-9.
Kuo HC. Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. Urology 2004;63:868-72.
Kuo HC, Liu SH. Effect of repeated detrusor onabotulinumtoxinA injections on bladder and renal function in patients with chronic spinal cord injuries. Neurourol Urodyn 2011;30:1541-5.
Chen YC, Kuo HC. The therapeutic effects of repeated detrusor injections between 200 or 300 units of onabotulinumtoxinA in chronic spinal cord injured patients. Neurourol Urodyn 2014;33:129-34.
Chen SF, Kuo HC. Therapeutic outcome and patient adherence to repeated onabotulinumtoxinA detrusor injections in chronic spinal cord-injured patients and neurogenic detrusor overactivity. J Formos Med Assoc 2015;114:583-9.
Chen SF, Chang CH, Kuo HC. Clinical efficacy and changes of urothelial dysfunction after repeated detrusor botulinum toxin a injections in chronic spinal cord-injured bladder. Toxins (Basel) 2016;8:E164.
Janzen J, Vuong PN, Bersch U, Michel D, Zaech GA. Bladder tissue biopsies in spinal cord injured patients: Histopathologic aspects of 61 cases. Neurourol Urodyn 1998;17:525-30.
McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 1981;126:205-9.
de Groat WC, Kawatani M, Hisamitsu T, Cheng CL, Ma CP, Thor K, et al. Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. J Auton Nerv Syst 1990;30 Suppl:S71-7.
Apodaca G, Kiss S, Ruiz W, Meyers S, Zeidel M, Birder L. Disruption of bladder epithelium barrier function after spinal cord injury. Am J Physiol Renal Physiol 2003;284:F966-76.
Jiang YH, Liu HT, Kuo HC. Urothelial dysfunction and chronic inflammation in patients with spinal cord injuries at different levels and correlation with urodynamic findings. Neurourol Urodyn 2015;34:757-62.
Birder LA. Role of the urothelium in urinary bladder dysfunction following spinal cord injury. Prog Brain Res 2006;152:135-46.
Collins VM, Daly DM, Liaskos M, McKay NG, Sellers D, Chapple C, et al. OnabotulinumtoxinA significantly attenuates bladder afferent nerve firing and inhibits ATP release from the urothelium. BJU Int 2013;112:1018-26.
Maggi CA, Meli A. The sensory-efferent function of capsaicin-sensitive sensory neurons. Gen Pharmacol 1988;19:1-43.
Fowler CJ, Beck RO, Gerrard S, Betts CD, Fowler CG. Intravesical capsaicin for treatment of detrusor hyperreflexia. J Neurol Neurosurg Psychiatry 1994;57:169-73.
Silva C, Rio ME, Cruz F. Desensitization of bladder sensory fibers by intravesical resiniferatoxin, a capsaicin analog: Long-term results for the treatment of detrusor hyperreflexia. Eur Urol 2000;38:444-52.
Kuo HC. Effectiveness of intravesical resiniferatoxin in treating detrusor hyper-reflexia and external sphincter dyssynergia in patients with chronic spinal cord lesions. BJU Int 2003;92:597-601.
Schurch B, de Sèze M, Denys P, Chartier-Kastler E, Haab F, Everaert K, et al. Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: Results of a single treatment, randomized, placebo controlled 6-month study. J Urol 2005;174:196-200.
MacDonald R, Monga M, Fink HA, Wilt TJ. Neurotoxin treatments for urinary incontinence in subjects with spinal cord injury or multiple sclerosis: A systematic review of effectiveness and adverse effects. J Spinal Cord Med 2008;31:157-65.
Ferreira RS, D'Ancona CAL, Oelke M, Carneiro MR. Intradetrusor onabotulinumtoxinA injections are significantly more efficacious than oral oxybutynin for treatment of neurogenic detrusor overactivity: Results of a randomized, controlled, 24-week trial. Einstein (Sao Paulo) 2018;16:eAO4207.
Mangera A, Andersson KE, Apostolidis A, Chapple C, Dasgupta P, Giannantoni A, et al. Contemporary management of lower urinary tract disease with botulinum toxin A: A systematic review of botox (onabotulinumtoxinA) and dysport (abobotulinumtoxinA). Eur Urol 2011;60:784-95.
Stoehrer M, Wolff A, Kramer G, Steiner R, Lmöchner-Ernst D, Leuth D, et al. Treatment of neurogenic detrusor overactivity with botulinum toxin A: The first seven years. Urol Int 2009;83:379-85.
Linsenmeyer TA. Use of botulinum toxin in individuals with neurogenic detrusor overactivity: State of the art review. J Spinal Cord Med 2013;36:402-19.
Cruz F, Herschorn S, Aliotta P, Brin M, Thompson C, Lam W, et al. Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: A randomised, double-blind, placebo-controlled trial. Eur Urol 2011;60:742-50.
Sussman D, Patel V, Del Popolo G, Lam W, Globe D, Pommerville P. Treatment satisfaction and improvement in health-related quality of life with onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity. Neurourol Urodyn 2013;32:242-9.
Sanford M. OnabotulinumtoxinA (Botox(®)): A review of its use in the treatment of urinary incontinence in patients with multiple sclerosis or subcervical spinal cord injury. Drugs 2014;74:1659-72.
Li GP, Wang XY, Zhang Y. Efficacy and safety of onabotulinumtoxina in patients with neurogenic detrusor overactivity caused by spinal cord injury: A systematic review and meta-analysis. Int Neurourol J 2018;22:275-86.
Huang M, Chen H, Jiang C, Xie K, Tang P, Ou R, et al. Effects of botulinum toxin A injections in spinal cord injury patients with detrusor overactivity and detrusor sphincter dyssynergia. J Rehabil Med 2016;48:683-7.
Kuo HC. Therapeutic outcome and quality of life between urethral and detrusor botulinum toxin treatment for patients with spinal cord lesions and detrusor sphincter dyssynergia. Int J Clin Pract 2013;67:1044-9.
Soler JM, Previnaire JG, Hadiji N. Predictors of outcome for urethral injection of botulinum toxin to treat detrusor sphincter dyssynergia in men with spinal cord injury. Spinal Cord 2016;54:452-6.
Mehta S, Hill D, Foley N, Hsieh J, Ethans K, Potter P, et al. A meta-analysis of botulinum toxin sphincteric injections in the treatment of incomplete voiding after spinal cord injury. Arch Phys Med Rehabil 2012;93:597-603.
Weckx F, Tutolo M, De Ridder D, Van der Aa F. The role of botulinum toxin A in treating neurogenic bladder. Transl Androl Urol 2016;5:63-71.
Wyndaele JJ, Van Dromme SA. Muscular weakness as side effect of botulinum toxin injection for neurogenic detrusor overactivity. Spinal Cord 2002;40:599-600.
Zakin E, Simpson D. Evidence on botulinum toxin in selected disorders. Toxicon 2018;147:134-40.
Schiavo G, Malizio C, Trimble WS, Polverino de Laureto P, Milan G, Sugiyama H, et al. Botulinum G neurotoxin cleaves VAMP/synaptobrevin at a single Ala-Ala peptide bond. J Biol Chem 1994;269:20213-6.
Montecucco C, Schiavo G. Structure and function of tetanus and botulinum neurotoxins. Q Rev Biophys 1995;28:423-72.
McMahon HT, Foran P, Dolly JO, Verhage M, Wiegant VM, Nicholls DG. Tetanus toxin and botulinum toxins type A and B inhibit glutamate, gamma-aminobutyric acid, aspartate, and met-enkephalin release from synaptosomes. Clues to the locus of action. J Biol Chem 1992;267:21338-43.
Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum
neurotoxins. Toxicon 2000;38:245-58.
Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: Implications for migraine therapy. Headache 2004;44:35-42.
Morris JL, Jobling P, Gibbins IL. Differential inhibition by botulinum neurotoxin A of cotransmitters released from autonomic vasodilator neurons. Am J Physiol Heart Circ Physiol 2001;281:H2124-32.
Khera M, Somogyi GT, Kiss S, Boone TB, Smith CP. Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int 2004;45:987-93.
Apostolidis A, Popat R, Yiangou Y, Cockayne D, Ford AP, Davis JB, et al. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol 2005;174:977-82.
Kanai A, Zabbarova I, Oefelein M, Radziszewski P, Ikeda Y, Andersson KE. Mechanisms of action of botulinum neurotoxins, β3-adrenergic receptor agonists, and PDE5 inhibitors in modulating detrusor function in overactive bladders: ICI-RS 2011. Neurourol Urodyn 2012;31:300-8.
Cho SY, Yi JS, Oh SJ. The clinical significance of poor bladder compliance. Neurourol Urodyn 2009;28:1010-4.
Birder LA, Nakamura Y, Kiss S, Nealen ML, Barrick S, Kanai AJ, et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci 2002;5:856-60.
Smith CP, Gangitano DA, Munoz A, Salas NA, Boone TB, Aoki KR, et al. Botulinum toxin type A normalizes alterations in urothelial ATP and NO release induced by chronic spinal cord injury. Neurochem Int 2008;52:1068-75.
Lucioni A, Bales GT, Lotan TL, McGehee DS, Cook SP, Rapp DE. Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU Int 2008;101:366-70.
Chen SF, Chang CH, Kuo HC. Effect of detrusor botulinum toxin a injection on urothelial dysfunction in patients with chronic spinal cord injury: A clinical and immunohistochemistry study before and after treatment. Spinal Cord 2016;54:889-94.
Giannantoni A, Mearini E, Del Zingaro M, Porena M. Six-year follow-up of botulinum toxin A intradetrusorial injections in patients with refractory neurogenic detrusor overactivity: Clinical and urodynamic results. Eur Urol 2009;55:705-11.
Hori S, Patki P, Attar KH, Ismail S, Vasconcelos JC, Shah PJ. Patients' perspective of botulinum toxin-A as a long-term treatment option for neurogenic detrusor overactivity secondary to spinal cord injury. BJU Int 2009;104:216-20.
Pannek J, Göcking K, Bersch U. Long-term effects of repeated intradetrusor botulinum neurotoxin A injections on detrusor function in patients with neurogenic bladder dysfunction. BJU Int 2009;104:1246-50.
Leitner L, Guggenbühl-Roy S, Knüpfer SC, Walter M, Schneider MP, Tornic J, et al. More than 15 years of experience with intradetrusor onabotulinumtoxina injections for treating refractory neurogenic detrusor overactivity: Lessons to be learned. Eur Urol 2016;70:522-8.
Kennelly M, Dmochowski R, Schulte-Baukloh H, Ethans K, Del Popolo G, Moore C, et al. Efficacy and safety of onabotulinumtoxinA therapy are sustained over 4 years of treatment in patients with neurogenic detrusor overactivity: Final results of a long-term extension study. Neurourol Urodyn 2017;36:368-75.
Koschorke M, Leitner L, Sadri H, Knüpfer SC, Mehnert U, Kessler TM. Intradetrusor onabotulinumtoxinA injections for refractory neurogenic detrusor overactivity incontinence: Do we need urodynamic investigation for outcome assessment? BJU Int 2017;120:848-54.
Akbar M, Abel R, Seyler TM, Bedke J, Haferkamp A, Gerner HJ, et al. Repeated botulinum-A toxin injections in the treatment of myelodysplastic children and patients with spinal cord injuries with neurogenic bladder dysfunction. BJU Int 2007;100:639-45.
Lombardi G, Musco S, Bacci G, Celso M, Bellio V, Del Popolo G. Long-term response of different Botulinum toxins in refractory neurogenic detrusor overactivity due to spinal cord injury. Int Braz J Urol 2017;43:721-9.
Prakash NS, Lopategui DM, Gomez C. Changes in management of poorly compliant bladder in botulinum toxin a era. Curr Urol Rep 2017;18:64.