AA

Botulinum Toxin Type A

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Botulinum toxin A (BTX-A) has been used for many disorders including strabismus, focal spasticity, hyperhydrosis, cosmetic disorders (wrinkles) and others. A newly approved indication in the USA and Canada is for NDO treatment in individuals with SCI and multiple sclerosis. Although anti-cholinergic medications remain first line therapy for this dysfunction, the advantage of botulinum toxin over systemic administration of medications is that botulinum toxin is used focally in the bladder; thus, it avoids systemic side effects, for the most part. There are various types of botulinum toxin available, including various types of BTX-A. When evaluating the literature in this area, one must be aware that although abobotulinumtoxin (AboBTx) and onabotulinumtoxin (OnaBTx) are both derived from BTX-A, they are very different and unit values cannot be compared or interchanged. There are also interesting clinical differences in using botulinum toxin for detrusor overactivity as opposed to spasticity and other neurological conditions; the effect of injecting into the detrusor lasts for 6-12 months, 2-3 times that expected for spasticity. Possible reasons for this is that 1) there is less or no peripheral nerve re-sprouting to reform the neuromuscular junctions in smooth muscle, and 2) the mechanism of blocking afferent C-fibre activity in the membrane bound vesicles of the afferent pathways and the urothelium is an additional effect to the traditionally understood blocking at the neuromuscular junction in the efferent pathway.

Table: Botulinum Toxin Type A

Discussion

In 2013, Mehta et al. published a large systematic review and meta-analysis examining the effect of botulinum toxin A on improving bladder function post SCI. In total, fourteen studies met inclusion criteria including one RCT (Schurch et al. 2005), one case-control (Grosse et al. 2009), and twelve pre-post studies (Schurch et al. 2005, Del Popolo et al. 2008, Game et al. 2007, Giannantoni et al. 2009, Klaphajone et al. 2005, Kuo et al. 2006, Kuo et al. 2008, Pannek et al. 2009, Tow et al. 2007, Wefer et al. 2010; Akbar et al. 2007, Patki et al. 2006). Ten studies examined OnaBTx and four studies examined aboBTx. The meta-analyses revealed large effect sizes and a significant increase in reflex detrusor volume (1, 3, 6 months, p<0.001 for all), bladder capacity (1, 3, 6, 12 months, p<0.001 for all), bladder compliance (1, 3, 6, 12 months, p<0.001 for all), and post-residual urine volume (1, 3, 6 months, p<0.001 for all). There was also a mean decrease in catheterization frequency (p<0.001) and number of incontinence episodes post treatment. Finally, Mehta et al. (2013) reported that there was no significant deterioration in maximum flow rate observed as a result of treatment (p=0.403). Three mild adverse effects were reported: hypertension (Tow et al. 2007), muscular weakness (Akbar et al. 2007), and stress urinary incontinence (Del Popolo et al. 2008). While this systematic review reported optimistic findings, it was unable to assess comparisons in botulinum toxin A type, different dosing schedules, control groups, or location sites.

Four RCTs have been published between 2007 and 2012 on the effectiveness of botulinum toxin for NDO post SCI; these studies were not included in the aforementioned systematic review and meta-analysis by Mehta et al. (2013). In a placebo-controlled RCT, Herschorn et al. (2011) examined the effect of 300U onaBTX injections into the intradetrusor to improve NDO. The authors found that onaBTX reduced incontinence episodes and maximum detrusor pressure during filling compared to controls (p<0.001 for both) at 6, 24, and 36 week follow-up. Similarly, void volume and cystometric capacity increased more for the treatment group compares to controls (p<0.001 for both). The authors reported minimal adverse effects such as muscle weakness and UTI. In a small RCT by Abdel-Meguid et al. (2010), subjects were randomized to receive onaBTX into either the intradetrusor only or both the intradetrusor plus intratrigonal. The authors reported improvements in all urodynamic parameters (incontinence episodes, complete dryness, reflex volume, cystometric capacity and maximum detrusor pressure) among both groups; however, only improvements in incontinence episodes, complete dryness and reflex volume were significantly greater in the combined group compared to the detrusor-only group (p<0.001 for all). Finally, a small RCT by Krhut et al. (2012) compared the effect of onaBTX to the detrusor versus suburothelial on a number of urodynamic parameters amongst a group of individuals with NDO secondary to SCI. The following urodynamic parameters improved for both groups, although there was no significant difference between groups: number of incontinent episodes, frequency of catheterizations, maximum detrusor pressure, void volume, cystometric capacity, and volume at first involuntary detrusor contraction. Krhut et al. (2012) reported favouring the suburothelial injections over the intradetrusor since injections could be better localized. Finally, one RCT demonstrated that onaBTX injected into the intradetrusor in either 200U or 300U produce greater improvements in quality of life (QoL) than individuals receiving the placebo (Schurch et al. 2007).

Two important RCTs (Cruz et al. 2011; Ginsberg et al. 2012) served as the basis for BTX-A being approved in Canada, the US, and Europe; however, the patient population is mixed, including individuals with SCI and multiple sclerosis. While this does not meet SCIRE inclusion criteria, it was felt that it was important to note these two RCTs as they have been pivotal in influencing the use of this treatment in clinical practice.

Conclusion

There is level 1a evidence (from several RCTs) that supports the use of onabotulinum toxin A injections into the detrusor muscle to provide targeted treatment for neurogenic detrusor overactivity and urge incontinence resistant to high-dose oral anticholinergic treatments with intermittent self-catheterization in SCI; numerous level 3 and 4 studies confirm the efficacy and safety.

There is level 4 evidence (from one pre-post and one case series study; Klaphajone et al. 2005; Caremel et al. 2011) that detrusor contractility may be decreased through repeated BTX-A injection. 

  • Onabotulinum toxin type A injections into the detrusor muscle improve neurogenic destrusor overactivity and urge incontinence; it may also reduce destrusor contractility.