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Botulinum Toxin

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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. BTX-A inhibits muscle contractions by preventing the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction. A more recent 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, an advantage of botulinum toxin versus systemic oral medications is that botulinum toxin is injected directly into the detruser, thereby minimzing systemic side effects. There are various types of botulinum toxin available, including several variations of BTX-A. While abobotulinumtoxin (AboBTx) and onabotulinumtoxin (OnaBTx) are both derived from BTX-A, they are important differences and unit values cannot be compared or interchanged. Only OnaBTx is approved for NDO. There are also interesting clinical differences when using botulinum toxin for NDO as opposed to spasticity and other neurological indications. As an example, the effect of injecting into the detrusor lasts for 6-12 months, 2-3 times that expected for spasticity. Possible reasons include 1) there is less or no peripheral nerve re-sprouting to reform the neuromuscular junctions in smooth muscle, and 2) there is a secondary mechanism of action comprised of blocking afferent C-fibre activity in the membrane bound vesicles of the afferent pathways and the urothelium in addition to the primary mechanism of blocking synaptic transmission at the neuromuscular junction in the efferent pathway. Blocking afferent C-fibre activity is especially important in NDO where afferent C-fibre overactivity after a spinal cord lesion is thought to be a significant contributor to the overactive reflex pathway.

Table: Botulinum Toxin

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 12 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 of botulinum toxin A type, different dosing schedules, control groups, or location sites. Unfortunately, many large randomized controlled trials were excluded from the meta-analyses due to having more individuals with MS than SCI individuals, even if they contain large numbers of individuals with SCI.

Seven RCTs were published between 2007 and 2016 addressing the effectiveness of botulinum toxin for NDO post SCI; which 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 compared to controls (p<0.001 for both). The authors reported minimal adverse effects such as muscle weakness and UTI. In three RCTs (Abdel-Meguid et al. 2010; Hui et al 2016; Huang et al 2016), subjects were randomized to receive onaBTX into either the intradetrusor only or both the intradetrusor plus intratrigonal. Abdel-Meguid et al (2010) 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). Although Hui et al (2016, n=96) and Huang et al (2016, n=80) both found higher rates of complete dryness in the combined group and that secondary urodynamic parameter (UI/day, voiding volume) improvements were more dramatic for the control group; they reported divergent I-QoL results for the experimental group. It is important to note both Huang et al. 2016b and Hui et al. 2016 found that injecting onabotulinum toxin 40 units to trigone, and 160 units to detrusor did not lead to more VUR compared to 200 units to trigone alone, and yet doing so decreased leak point pressure. It is not clear, however, what individual groups were tested and how many were already on IC versus voluntary emptying with spontaneous void, and how many had improvement with emptying with voluntary spontaneous void.  The latter would have been the main reason to decrease leak point pressure as decreasing detrusor leak point pressure (DLPP) in individuals performing IC would not be beneficial.

Despite these beneficial effects, Leitner et al (2016) reported that almost 40% of individuals discontinue onaBTX usage over time.  Twenty-one percent of individuals discontinued due to lack of clinical and/or urodynamic response and 19% preferred to switch to another treatment (antimuscarinics and/or neuromodulation). Discontuation likely is not related to effects on cardiac function. A pre-post study (Fougere et al. 2016, n=17) found that intradetrusor injections of 200 units onabotulinumtoxin actually reduced episodes of autonomic dysreflexia and elevations in blood pressure during urodynamic studies.  Another case series of 99 individuals (Soler et al 2016) also confirmed the disappearance or improvement of autonomic dysreflexia in 70% of individuals treated successfully for detrusor sphincter dyssynergia (DSD) resulting from NDO.

A small RCT by Krhut et al. (2012) compared the efficacy of onaBTX administered to the detrusor versus suburothelium for NDO secondary to SCI. There was no significant differences between groups for 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.

Two RCTs demonstrated that onaBTX injected into the detrusor in either 200U or 300U produce similar improvements in CBC, PVR, Qmax (Chen et al 2014) and quality of life (QoL) was reported as equivocal for both doses by Chen et al (2014) and improved over the placebo group as reported by Schurch et al. 2007. Additional pre-post studies of individuals refractory to antimuscarinic agents for the treatment of NDO reported onaBTX related improvement in both clinical efficacy (Chen & Kuo 2015) and QoL for more than eight months (Al Taweel et al 2015, n=103).  This latter study also reported a reduction or discontinuation in oral anticholigergic use as a result of onaBTX administration. OnaBTX was also effective in individuals refractory to intravesical oxybutynin administration. (Alvares et al, 2014). Additional pre-post studies (Yang et al 2015; Ge et al 2015) and case series (Gutierrez-Martin et al 2015) add to the body of evidence for improved bladder function following onaBTX administration; even in the event of a first failed injection (Peyronnet et al 2016).

In a retrospective study by Anquetil et al. 2016 comparing intradetrusor botulinum toxin to augmentation cystoplasty, botulinum toxin resulted in fewer complications and improved quality of life; however, augmentation cystoplasty was slightly better for decreasing incontinence and improving cystometric capacity.

Two important RCTs (Cruz et al. 2011; Ginsberg et al. 2012) served as the basis for the regulatory approval of BTX-A in Canada, the US, and Europe; however, the study populations included individuals with both SCI and multiple sclerosis. While these studies did not meet SCIRE inclusion criteria, it was nevertheless important to note these two RCTs as they have been pivotal in influencing the use of this treatment both in clinical practice and research. Ginsberg et al. (2013) reported the SCI subanalysis of these studies (Cruz et al. 2011; Ginsberg et al. 2012); which form the largest analysis of double-blind placebo-controlled trials for NDO in SCI. Results confirmed a dramatic improvement in continence and quality of life following the administration of onabotulinum toxin.

Conclusion

There is level 1a evidence (from several RCTs: Abdel-Meguid et al (2010); Kruhut et al 2012; Hui et al 2016; Huang et al 2016; Ginsberg 2012) that supports the injection of onabotulinum toxin A into the detrusor muscle to provide targeted treatment for SCI – related neurogenic detrusor overactivity resistant to oral anticholinergic treatments. Benefits include decreased incontinence, improved bladder capacity, decreased detrusor pressure, improved quality of life, amongst other findings. Numerous level 3 and 4 studies confirm the efficacy and safety. 

Dosages of 200U versus 300U onaBTX are non-superior for symptom and QoL improvement secondary to NDO; as supported by level 2 evidence from 2 less rigorous RCTs (Schurch et al 2007; Chen et al 2014). There are higher retention rates with 300U, thus 200U is the recommended dosing (Ginsbger et al. 2012).

The superiority of Intradetrusor botulinum toxin compared to augmentation cystoplasty is supported by level 2 evidence. Advantages of intradetrusor botulinum include fewer complications and better quality of life; even though augmentation cytoplasty was better at decreasing incontinence and improving cystometric capacity.

There is level 4 evidence that onaBTX may improve NDO in individuals that are refractory to anticholinergics (Chen & Kuo 2015; Al Taweel et al 2015; Alvarez et al 2014).

Level 4 evidence is available for onaBTX administration as the basis for reducing (Soler et al 2016) or eliminating (Fougere et al 2016; Soler et al 2016) autonomic dysreflexia while improving NDO symptoms.

There is level 4 evidence from one pre-post study and one case series (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, intradetrusor pressures, bladder capacity and urge incontinence; it may also reduce destrusor contractility.