Abstract
Botulinum neurotoxin has been shown to be effective when used in the management of lower urinary tract dysfunction, prostatic disorders and more recently vaginismus in women suffering with pelvic floor muscle tension. Here we provide an overview of the use and efficacy of botulinum toxin in these conditions.
Keywords
Introduction
Clostridium botulinum is a Gram-positive, anaerobic spore-forming bacterium whose growing cells secrete botulinum neurotoxin (BTX), the most poisonous of all known poisons. BTX has significant clinical applications as an effective treatment for involuntary muscle disorders such as bepharospasm, strabismus, hemifacial spasm and certain types of spasticity in children as well as severe hyperhidrosis and cosmetically for the treatment of glabellar lines. 1 Among seven serotypes of BTX only type A (Botox, Dysport and Vistabel) and type B (NeuroBloc) are available for clinical use. Although both BTX types are available, type A is most frequently used in clinical practice when compared with type B; the latter being indicated only for spasmodic torticollis (cervical dystonia). Despite the clinical potential for both types to be similar, the human muscle paralysis from BTX type B is not as complete or long-lasting as that resulting from BTX type A. 2
BTX type A has a complex mechanism of action that results in muscle relaxation. At the neuromuscular junction, the pre-synaptic nerve ending is filled with vesicles containing acetylcholine while there are acetylcholine receptors at the post-synaptic muscle membrane. Synaptic vesicles fuse with the membrane in response to an elevation of intraneuronal calcium concentration and undergo release of their transmitter by exocytosis. Intracellular proteins that contribute to the fusion of these vesicles with the plasma membrane during exocytosis include synaptosomal protein (synaptobrevin) and vesicle-associated membrane protein (syntaxin). Through the proteolytic action of these proteins, botulinum toxins prevent exocytosis thereby inhibiting the release of acetylcholine. BTX type A does not lead to persistent histological changes in the nerve terminal of the target muscle. 3
Clinical trials have shown an incidence of local adverse events of approximately 25% in BTX type A-treated patients when compared with 15% in a control group. 3 Focal weakness is the only adverse event to occur more often following BTX type A and, despite high total body doses used over multiple muscle groups and injection sites, systemic side-effects are rare. 3 The greatest concern with the use of BTX is the formation of blocking antibodies leading to non-response of subsequent treatments, which can appear in some patients only after a few injections. Epitome-mapping studies have shown that several factors can influence the immune response to the toxin, including dose, duration of treatment, frequency of immunization and quality of the toxin. 4 Antibodies against BTX are neutralizing or blocking and directly interfere with botulinum toxin's biological mechanism of action. 5 Complete antibody-induced treatment failure is usually preceded by a series of injections in which the therapeutic effect is reduced in intensity and duration. 5 This usually occurs within two or three years after initiation of BTX. Once a patient becomes immunoresistant to one toxin then switching to another toxin will most often be of limited and short-lived benefit.
Lower urinary tract dysfunction
BTX has been investigated for the treatment of various lower urinary tract dysfunctions. Initially this was employed in the treatment of neurogenic detruser overactivity in spinal cord injured patients and later extended to the treatment of idio-pathic detruser overactivity. BTX injection temporarily blocks the presynaptic release of acetylcholine from the parasympa-thetic innervation and produces a paralysis of the detruser smooth muscle. The efficacy of the treatment exceeds that expected from simple detruser muscle paralysis with an effect of reduced urgency of micturition. 6
Early studies compared the efficacy of intravesical BTX with either intravesical lidocaine. 7 or resiniferatoxin. 8 in the treatment of neurogenic detruser overactivity. In each study BTX was found to have superior clinical and urodynamic benefit. Such efficacy for BTX has been confirmed in recent studies. In a randomized, placebo-controlled, double-blind study of 31 patients with neurogenic detruser overactivity due to spinal cord injury, myelo-meningocele, trauma at birth, multiple sclerosis and myelitis of another cause, a single intravesical injection of 500 U of BTX type A was shown toreduce high detruser pressure and frequency of urinary leakage during the 26-week study period. 9 Quality of life parameters were significantly improved in the BTX-treated group when compared with those who received placebo. 9 A further randomized, placebo-controlled, double-blind study to evaluate the impact of 300 U of BTX type A in 59 patients with neurogenic urinary incontinence, using the incontinence Quality of Life Questionnaire showed significant improvement in health-related quality of life. 10 BTX type A has been used in a studyofchildren, havingamean ageof5.6years, with neuropathic bladder refractory to medical treatment. After cystoscopic treatment with BTX, nine of the 16 incontinent children showed complete continence after treatment while four reported mild to moderate improvement and three showed no improvement. 11
In recent years there has been an increasing use of BTX for the management of conditions characterized by detrusor overactivity.12,13 In a randomized, placebo-controlled, double-blind study of BTX type A (200 U intradetrusor injection) in the treatment of idiopathic detrusor overactivity, significant increases in maximum cystometric capacity were observed at four weeks and 12 weeks in 16 patients treated with BTX when compared with 18 receiving placebo. 14 In the BTX-treated group, there was a significant reduction in urinary frequency and urgency, as well as a significant improvement in quality of life (as measured by the Incontinence Impact Questionnaire and Urogenital Distress Inventory). 14 In a study of 27 patients with idiopathic low detrusor contractility and voiding dysfunction there was recovery of detrusor contractility in 13 (48%) after a single urethral injection of BTX type A (100 U) and of these, five had a positive long-term effect for more than one year. 15 Patients with normal bladder sensation combined with poor relaxation or hyperactive urethral sphincter were significantly more likely to recover normal detrusor function. 15
A dose-ranging study using sub-urothelial injections of different doses of BTX type A in idiopathic, refractory detrusor overactivity has shown 100 U to be as effective and with significantly less-adverse events when compared with 150 U or 200 U. 16 Comparison of the effectiveness of detrusor, sub-urothelial and bladder base injections of BTX type A in patients with detrusor overactivity has indicated the former to be most effective. 17 Generalized adverse events after intravesical injections of BTX type A are rare. 18 compared with BTX type B in which autonomic side-effects after injection suggest systemic spread of the toxin. 19
Although most studies have small numbers of participants there is overwhelming evidence for the efficacy, safetyandtolerabilityof BTX, specifically type A, for the management of detrusor over-activity as well as treating interstitial cystitis. 20 However, further large randomized, placebo-controlled trials are required to determine the ideal conditions for the use of BTX.
Prostatic disorders
The use of BTX has been extended to the treatment of symptomatic benign prostatic hyperplasia (BPH). However, the actual mechanism through which BTX improves symptoms, post-void residual volume, maximal urinary flow rates and prostatic size remains unknown.21,22
An early randomized, placebo-controlled study reported that a single injection of BTX type A (200 U) was a safe, effective and well-tolerated treatment in men with voiding dysfunction due to BPH. 23 In this study, the outcome of each group was evaluated by comparing symptom scores, serum prostate-specific antigen (PSA) concentration, prostate volume, postvoid residual urine volume and peak urinary flow rates. In men who received BTX, the symptom score reduced by 65% when compared with baseline values and serum PSA by 51% from baseline. In the placebo group, there was no significant change in symptom score or PSA levels from baseline. No local complications or systemic adverse events were observed in study participants. However, the number of patients enrolled in the study was small (30 participants).
Further studies have confirmed the benefit and safety of using a single intraprostatic injection of BTX type A in men with BPH refractory to standard medical treatment.24,25 In a study of 16 men with symptomatic BPH, a prostate volume < 30 cm3 and peak flow rate < 12 mL/s who received a single intraprostatic injection of BTX type A (100U) there was a sustained (at 12-months follow-up) subjective improvement in symptoms beginning within one week and a reduction in mean prostatic volume of 13.3% and improved maximal urinary flow rate increased by 39.8%. 24 Results were confirmed in a later study in which 41 men with symptomatic BPH were injected with BTX type A (100 U for those with a prostate volume < 30 mL, 200 U for those with a prostate volume > 30 mL) after which there was an improvement in quality of life indices (>30% in 31 men) and improvement in maximum urinary flow rate which was sustained at 12 months. 25 Both studies concluded that intraprostatic injection of BTX type A was a safe and effective treatment for men with symptomatic BPH.
Several studies have been focused on men with symptomatic BPH who are refractory to medical treatment and who are poor surgical candidates. Improvement of spontaneous voiding, decreased voiding pressure and postvoid residual volume was seen in 10 men following a single intraprostatic injection of BTX type A (200 U). 26 Similar findings were observed in a study of 21 men who had had an in-dwelling catheter for at least three months because of BPH and who received a single intraprostatic injection of BTX type A (200–U); 76% of men could resume voiding at one month post-treatment 27
In a recent study, various doses of capsaicin was injected into the prostate of adult male rats to simulate non-bacterial prostatitis. 28 The prostate was removed after 30 minutes for histology and to assess cyclooxygenase (COX) 2 protein concentration. Rats that received intraprostatic BTX type A (20 U) one week prior to capsaicin showed significantly reduced inflammatory cell accumulation, COX 2 expression and reduced pain behaviour. The authors supported the subsequent clinical evaluation of BTX in men with prostatitis.
The current literature suggests a novel mechanism of action of BTX in the treatment of BPH and possibly non-bacterial prostatitis. However, larger, randomized, placebo-controlled studies need to be performed and more research is required in identifying the mechanisms by which BTX affects the prostate.
Pelvic floor muscle tension
BTX type A has been injected into the levator ani muscles of women with pelvic floor spasm producing a marked alleviation of symptoms.29,30 In a study, 12 women with objective pelvic floor muscle hypertonicity and a minimum two-year history of chronic pelvic pain were given BTX type A (40 U) bilaterally into the puborectalis and pubococcygeus muscles under conscious sedation. 29 Median visual analogue scale (VAS) scores were significantly improved for dyspareunia and dysmenorrhoea with a non-significant reduction in non-menstrual pelvic pain. Pelvic floor muscle manometry showed a 37% reduction in resting pressure at week 4 and at least a 25% reduction was maintained at week 12. Sexual activity scores showed a significant reduction in discomfort. The same authors conducted a second study which was double-blind, randomized, placebo-controlled in which 60 trial participants received either BTX type A (80 U) or saline injected into the pelvic floor muscles. 30 There was a significant change from baseline in VAS in the BTX-treated group for dyspareunia and non-menstrual pelvic pain, while in the placebo group only dyspareunia was significantly reduced from baseline. There was a significant reduction in pelvic floor pressure in the BTX-treated group.
BTX type A has been used successfully to treat severe (third or fourth degree) vaginismus in women refractory to conventional treatments. 31 Twenty-four study participants had BTX type A (150–400 U) injected bilaterally into the puborectalis muscles in three separate sites. Subjective vaginal examination one week after treatment showed little or no evidence of vaginismus in the majority of women, while 75% achieved satisfactory intercourse. Symptomatic improvement was sustained during the 12-month follow-up period.
An attempt to use BTX type A (20 U or 40 U 12-weekly) to relieve coital pain, reduce pelvic floor tension and reduce vestibular hyperalgia had been used in two women with vestibu-lodynia. 32 Outcomes included a VAS, weekly coital pain diaries, surface electromyography and a vulval algesiometer. BTX modestly reduced coital pain in one woman, but was ineffective in the other. Pelvic floor hypertonicity was markedly reduced in both women but there was a negligible change in vestibular hyperalgia.
Conclusion
Over the last five years, BTX type A has been used successfully, with few systemic adverse events, in a variety of urogenital conditions in which at least part of the aetiology has been muscle over-activity. However, there are a few randomized, placebo-controlled clinical trials sufficiently powered to recommend BTX as a standard treatment in these conditions. Despite this, information on BTX is available to the public on support group websites, e.g. www.vaginismus.com, www.vaginismus-awareness-network.org, www.prostatitis.org. Clinicians treating such groups of patients may well find themselves being asked about BTX by an increasingly well-informed population.