Botulinum Toxin
Botulinum toxin is an exotoxin produced by the bacteria Clostridium botulinum. As noted previously (see 3.1.2 Toxin Therapy for SCI-Related Detrusor Overactivity), it has been used for many conditions associated with muscular overactivity and specifically for NDO. Among individuals with sphincter overactivity post SCI, botulinum toxin may be administered into the external urethral sphincter causing the muscle to relax resulting in improved drainage (DeSeze et al. 2002). The toxin works by inhibiting acetylcholine release at the neuromuscular junction and relaxing the muscle, an effect that gradually wears off over the months following injection. Injections of botulinum toxin A into the sphincter may improve emptying and possibly eliminate the need for catheterization.
Discussion
Detrusor external sphincter dyssynergia and associated high bladder pressures, vesicoureteral reflux, and frequent UTIs are associated with poor long-term outcomes in persons with SCI. These individuals may develop upper tract deterioration and/or suffer incontinence and poor QoL. Injection of botulinum toxin into the external urethra reduces bladder pressures, improves the incidence of UTI, and in some individuals, normalizes bladder emptying (Tsai et al. 2009; Kuo 2008). The impact of increased incontinence after sphincter injection, along with improved urodynamic parameters were studied by Kuo (2008; 2013). While this author cautions that QoL can decrease due to increased incontinence experienced by some individuals, careful individual selection and combinatorial approaches may allow some to benefit from the clearly evident improvement in urodynamic parameters and UTI incidence. Tsai et al. (2009) showed statistically significant improvement in QoL post-injection but did not reveal data on incontinence. Huang et al. (2016) also showed significantly improved QoL as well as data demonstrating complete dryness in all participants at 2 weeks sustained at 8 and 16 weeks.
Kuo (2013) found that combined detrusor and additional low-dose urethral sphincter BTX-A injections in individuals with incomplete SCI and detrusor sphincter dyssynergia, was effective in producing less urinary incontinence and preservation of spontaneous voiding. As well, participants with detrusor sphincter dyssynergia treated only with detrusor BTX-A injections (i.e. 200 U) improved QoL ratings to a greater extent than participants treated with only urethral injections (i.e. 100 U). Yang et al. (2016) performed transrectal ultrasound-guided catheter transurethral injections (100U) into the external urethral sphincter to treat DESD and achieved a success rate of 75.2%. In a case series of 99 individuals who received urethral injections of botulinum toxin to treat DSD, good outcomes were observed in 89% of participants; were the presence of detrusor contractions and normal bladder neck activity were strong predictors of good outcomes (Soler et al. 2016).
The improvements found in post-voiding residual volumes demonstrated by Kuo (2008, 2013) and Tsai et al. (2009) were initially demonstrated by DeSeze et al. (2002); who conducted a double blind RCT in which lidocaine as a control injection (n=8) was compared to botulinum toxin A (BTxA) as active treatment (n=5). DeSeze et al. (2002) found BTxA improved post void residual volume in individuals with SCI to a greater extent than lidocaine. One month following the injection of BTxA into the external sphincter, post-void residual volume decreased significantly from 159.4 mL to 105.0 mL and participants who previously presented with autonomic dysreflexia no longer exhibited symptoms.
In the clinical setting, a test dose of BTX-A combined with integrated electromyography is the optimal method for evaluation of dose and efficacy. Chen et al. (2010) demonstrated that a single low dose (100 U) of BTX-A, applied into the external urethral sphincter cystoscopically, could be monitored 4 weeks post-injection for objective measures of efficacy. Severe urethral sphincter spasticity as documented through integrated electromyography served as an indication for repeat injections or higher doses. Additional studies demonstrated a decrease in symptoms of autonomic hyperreflexia in at least 60% of participants (Tsai et al. 2009, Kuo 2008, Dykstra et al. 1988; Dykstra & Sidi 1990; Petit et al. 1998; Schurch et al. 1996). Almost all participants showed post-injection sphincter denervation on electromyography resulting in temporary relief of these symptoms for approximately 2-3 months; afterwhich additional subsequent BTxA injections were needed to maintain results (Dykstra et al. 1988; Dykstra & Sidi 1990).
Schurch et al. (1996) compared the effectiveness of transurethral versus transperineal botulinum toxin A injections in a prospective controlled study. The study found that transurethral botulinum toxin injections were more effective in reducing urethral pressure than transperineal injections. However, other symptoms were improved with either injection method. Tsai et al. (2009) described a method of transperineal sphincter injections using fluoroscopic guidance and electromyography that dramatically improved bladder emptying, with most individuals returning to voiding. Participants were able to avoid frequent ICs with three being able to discontinue indwelling catheterization altogether.
Schurch et al. (1996) also revealed the additive effects of recurrent BTx injections resulting from the prolonged inhibition of acetylcholine release. After 3 monthly injections, the therapeutic effects of BTx lasted as long as 9 months compared to only 2-3 months with 1 injection. Women, as a result of anatomical differences, often have greater difficulty performing self-catheterization than do men. Therefore the “normalization” of voiding as a result of botulinum toxin injections into the sphincter may play an even greater role in the urologic management of females with SCI. Phelan et al. (2001) were the first to demonstrate the successful use of botulinum toxin A in women. Their study of 13 females showed that all but one was able to spontaneously void following botulinum A injection. More study of the long term outcomes of “spontaneous voiding” after sphincter injection in women is required.
Chen et al. (2010) evaluated the effects of a single transrectal ultrasound-guided transperineal injection of 100 U onaBTx to the external urethral sphincter to treat DESD. As the prostate gland represented a key landmark in the transrectal ultrasound-guided injection, the study was limited to male subjects. Video-urodynamic results obtained at an average of 33.3 days post-injection showed significant reduction in dynamic urethral pressure, integrated electromyography, and static urethral pressure. The onaBTx injection did not produce a significant decrease in maximal detrusor pressure. This was the first study to demonstrate the effect of transrectal ultrasound -guided transperineal onaBTx injection into the external urethral sphincter and the potential for achieving outcomes similar to transurethral injection.
While not specifically mentioned in the above studies, a group of individuals likely to benefit from injections of BTX-A into the sphincter are men who have persistently elevated bladder volumes while using condom drainage. Reasons why individuals with SCI chose condom drainage include a reluctance to perform self catheterization or alternatively there is persistent incontinence on IC regimes despite adequate trials of anticholinergic medication. These individuals could theoretically benefit from improved drainage, as residual urine is a common cause of UTI, and accompanying elevated bladder pressures place the upper genitourinary tracts at risk. Whether or not such individuals actually resume “voiding” to allow for the discontinuation of condom drainage altogether has not been addressed.
Botulinum toxin therapy is advantageous as it allows one to avoid major surgical procedures and their associated risks. Botulinum toxin injections decrease the resistance to urine outflow by relaxing the external sphincter. This in turn decreases post-void residuals in 70% of individuals, with acceptable voiding pressures (Tsai et al. 2009). Symptoms such as autonomic dysreflexia and UTI incidence also appear to be reduced. Sphincter denervation, however, is transient and repeated injections are required to maintain therapeutic results. Post-injection urodynamic studies should be conducted to document that resultant voiding pressures fall in the acceptable range. For individuals with SCI with neurogenic bladder that do not experience unacceptable incontinence, botulinum toxin injections into the external sphincter can improve bladder emptying. Further study is required to determine whether or not recurrent sphincter injections and related improvements in voiding pressures and UTI incidence result in better long term upper tract outcomes. Furthermore, to ensure widespread clinical uptake studies are needed to identify the individuals who are best suited to maximize the benefits of sphincter injections while avoiding unacceptable incontinence.
Conclusion
There is level 1 evidence (from one RCT and several controlled and uncontrolled trials: DeSeze et al. 2002) that botulinum toxin injected into the external urinary sphincter may be effective in improving outcomes associated with bladder emptying in persons with neurogenic bladder due to SCI.
There is level 4 evidence (from one case series: Soler et al 2016) that the presence of detrusor contractions and normal bladder neck activity may be strong predictors of good outcomes for urethral injections of botulinum toxin to treat DSD.
