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Botulinum Toxin for Bladder Emptying

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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.

Table: Bladder Emptying through Botulinum Toxin

Discussion

Detrusor external sphincter dyssynergia and associated high bladder pressures, vesicoureteral reflux, and frequent UTIs are associated with poor long-term outcomes for patients. These patients may develop upper tract deterioration and/or suffer incontinence and poor QoL. Injection into the external urethra with botulinum toxin has been shown to reduce bladder pressures, improve incidence of UTI, and in some patients, normalize bladder emptying (Tsai et al. 2009; Kuo 2008). The important impact of increased incontinence after sphincter injection, along with 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 patient 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.

Kuo (2013) found that combined detrusor and additional low-dose urethral sphincter BTX-A injections in patients with incomplete SCI and detrusor sphincter dyssynergia, was effective in producing less urinary incontinence and preservation of spontaneous voiding. As well, patients with detrusor sphincter dyssynergia and treated only with detrusor BTX-A injections (i.e., 200 U) improved QoL ratings significantly more so than patients treated with only urethral injections (i.e. 100 U).

The improvement found in post-voiding residual volume demonstrated by Kuo (2008, 2013) and Tsai et al. (2009) was initially desmontrated by DeSeze et al. (2002) who conducted a double blind RCT using lidocaine as a control injection (n=8) compared to botulinum toxin A (BTxA) as the active treatment (n=5). DeSeze et al. (2002) found BTxA improved post void residual volume in individuals with SCI significantly better than lidocaine. One month after BTxA was injected into the external sphincter, post-voiding residual volume decreased significantly from 159.4 mL to 105.0 mL; all patients 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 would advocate for repeated injections or higher doses. Other studies also show a decrease in symptoms of autonomic hyperreflexia in at least 60% of patients (Tsai et al. 2009, Kuo 2008, Dykstra et al. 1988; Dykstra & Sidi 1990; Petit et al. 1998; Schurch et al.1996). Almost all patients showed post-injection sphincter denervation on electromyography resulting in temporary relief of these symptoms for approximately 2-3 months leading to the need for subsequent BTxA injections 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 significantly more effective in reducing urethral pressure than transperineal injections. However, other symptoms were improved through either injection method. Tsai et al. (2009) described a method of transperineal sphincter injections using fluoroscopic guidance and electromyography that resulted in excellent effects on bladder emptying, with most patients returning to voiding. Patients were able to avoid frequent IC and three patients were able to discontinue indwelling catheterization altogether.

Schurch et al. (1996) also revealed the additive effects of recurrent BTx injections resulting from prolonged inhibition of acetylcholine release. After 3 monthly injections, the therapeutic effects of BTx lasted for as long as 9 months compared to only 2-3 months with 1 injection. Women, as a result of anatomial differences, often have greater difficulty performing self-catheterization than do men. Therefore voiding “normalization” as a result of sphincter injection with botulinum toxin may have an even more significant 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. This study of 13 females showed that all but one patient was able to spontaneously void after botulinum A injection. More study on the long term outcome 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 postinjection 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 patients likely to benefit from injections of BTX-A into the sphincter are those men who have persistently elevated bladder volumes while using condom drainage. Sometimes such patients have chosen condom drainage because of reluctance to perform self catheterization while other times this bladder drainage option is chosen because of persistent incontinence on IC regimes despite adequate trials of anticholinergic medication. These patients could theoretically benefit from improved drainage, as residual urine is a common cause of UTI, and can also accompany elevated bladder pressures, that put upper tracts at risk. Whether or not such patients 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 therapy injection relaxes the external sphincter resulting in a decrease in post-voiding residual urine volume, and in 70% of patients, acceptable voiding pressures (Tsai et al. 2009). This improvement further seems to result in reducing other symptoms such as autonomic dysreflexia and UTI incidence. However, due to transient sphincter denervation, it has the disadvantage of requiring repeated injections to maintain therapeutic results. Post-injection urodynamic studies should be conducted to prove that resultant voiding pressures are in the acceptable range. For individuals with SCI with neurogenic bladder that do not experience unacceptable incontinence, botulinum toxin injection into the external sphincter is effective in assisting with more effective bladder emptying. Whether or not recurrent sphincter injection related improvements in voiding pressure and UTI incidence results in better long term upper tract outcomes requires further study. Furthermore, clarity in which patients are best suited to maximize the benefits of sphincter injections without subsequent unacceptable incontinence is needed in future studies to ensure widespread clinical uptake.

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. 

  • Botulinum toxin injected into the sphincter is effective in assisting with bladder emptying for persons with neurogenic bladder due to SCI.