Welcome to SCIRE Professional
 

Enhancing Bladder Volumes Pharmacologically – Botulinum Toxin

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 2 Botulinum Toxin Therapy for SCI-Related Detrusor Overactivity

Author Year

Country
Research Design
Score
Total Sample Size

MethodsOutcome
Mehta et al. 2013

Canada

Meta-analysis & Systematic Review

AMSTAR=9

N=14 studies

Methods: A meta-analysis was conducted to examine the effectiveness of BTX-A on neurogenic detrusor overactivity (NDO) in people with SCI. The following databases were searched: MEDLINE, CINAHL, EMBASE and PsycINFO for all relevant articles from 1980 to June 2012. Keywords included: spinal cord injury, paraplegia,

quadriplegia, tetraplegia, bladder, detrusor, botulinum toxin, Botox,

onabotulinumtoxin, abobotulinumtoxin, and BTX-A.

The following inclusion criteria were used:

1.     BTX-A was injected into the detrusor wall with the aim of improving NDO. Studies with single and multiple injections were included.

2.     BTX-A was compared with a placebo or active treatment, or in the absence of a control condition, subjects received BTX-A and were assessed before and after treatment.

3.     At least 50% of participants in the study had an SCI, and a minimum of 3 participants had an SCI.

4.     Participants were 18 yr or older.

Data was analyzed in each of the studies by calculating a standardized mean difference, and a 95% confidence interval for the following outcomes: reflex detrusor volume, bladder capacity, bladder compliance, catheterization frequency, max flow rate, and post-residual volume when applicable; where effect sizes were small (>0.2), moderate (>0.5) or large (>0.8).

1.     Fourteen studies met the inclusion criteria.

2.     The average ages of the participants range from 32.5 yr to 49.9 yr. Of the 10 studies that did report the number and women in the study, there were a total of 324 men and 196 women. The time since injury ranged from 4.5 to 13.3 yr.

3.     Ten studies used injections of OnaBTx at 200-300 U in 15-40 sites in the bladder. While four studies used aboBTx injections of 750 or 1000 units into the detrusor wall at 30 to 40 sites.

4.     Large effect sizes and significant increases in the outcomes of interest were apparent in reflex volume, bladder capacity, bladder compliance, post residual volume, and a mean decrease in catheterization frequency (p<0.01).

5.     Rate of incontinence episodes decreased from 23.1% to 1.31% after BTX-A treatment.

6.     No significant decreases in max flow rate was observed for those that could void (p=0.403).

 

Karsenty et al. 2008

France

Systematic Review

AMSTAR=9

N=18 studies

Methods: A MEDLINE and EMBASE search for clinical studies with BTX-A injected into the detrusor of adults with neurogenic detrusor overactivity was performed. Databases were searched from 1993 to March 2007 with the following medical subject heading (MeSH) terms: “Urinary bladder, Neurogenic” and “Botulinum Toxin Type A”; with the following filters: “human”, “clinical trial”, and “adult, 19+yr”.1.     18 articles were selected. The amount of BTX-A was mostly 300U usually as 30 injections.

2.     The majority of studies reported significant clinical improvements (40-80% of individuals became completely dry between clean IC).

3.     Improvements in urodynamic parameters were also noted: maximum detrusor pressure was reduced to <40 cmH2O in the majority of studies.

4.     Quality of life increased.

5.     There were no major adverse events in the majority of studies.

De Laet and Wyndaele 2005

Belgium

Systematic Review

AMSTAR=2

N=4 studies

Methods: Authors searched pubmed for adverse events after BTX-A injections for lower urinary tract dysfunction. The following keywords were used: “botulinum toxin”, “bladder”, “external”, “urethral sphincter”, “lower urinary tract”, “adverse events”, “complications” and “general muscle weakness”.Four publications were found reporting adverse events following local injection of BTX-A in the lower urinary tract:

1.     Dykstra and Sidi after injecting 5 SCI individuals with detrusor-sphincter dyssynergia; 3/5 experienced generalized upper extremity weakness after initial injections.

2.     Del Popolo reported hypostenia in 5/61 individuals that were treated with 300 U of onaBTx or 1000 U of aboBTx at 20-30 different sites in the detrusor muscle.

3.     Kuo injected 50-100 U of BTX-A in the external urethral sphincter of 20 individuals, one individual had high fever lasting 2 wk after the injection.

4.     In a study conducted by the authors, two cases of general muscle weakness after BTX-A injection were reported.

Denys et al. 2017

France

RCT

PEDro=6

N=47

Population: Dysport 15: Mean age=41.1±12.1yr; Gender: males=7; females=7; Etiology: SCI=9; Multiple Sclerosis=5.

Placebo 15: Mean age=46.5±10.7yr; Gender: males=4; females=2; Etiology: SCI=4; Multiple Sclerosis=2.

Dysport 30: Mean age=50.5±11.1yr; Gender: males=4; females=12; Etiology: SCI=7; Multiple Sclerosis=9.

Placebo 30: Mean age=40.8±10.6yr; Gender: males=4; females=2; Etiology: SCI=2; Multiple Sclerosis=4.

Intervention: Individuals were randomized into one of four groups: Dysport 15 injection sites; Placebo 15 injection sites; Dysport 30 injection sites; Placebo 30 injection sites. Subjects were injected with 750 U of BoNT-A-hemagglutinin complex in either 15 or 30 intradetrusor sites (sparing the trigone).

Outcome Measures: Incontinence episode frequency (IEF); Maximum cytometric capacity; maximum detrusor pressure; reflex volume at first detrusor contraction; compliance. Outcome measures were assessed at baseline, 14, 42, and 84d follow-ups.

1.     Dysport 15 was equally effective as Placebo 15 at altering IEF, reflex volume at first detrusor contraction, and compliance at all time points (p>0.05).

2.     Dysport 15 was more effective than Placebo 15 at decreasing maximum detrusor pressure, but only at the 42 and 84d follow-ups (p<0.05). At the 14d follow-up, both groups were equally effective (p>0.05).

3.     Dysport 15 was also more effective than Placebo 15 at increasing cystometric capacity, but only at 14 and 84d follow-ups (p<0.05).

4.     There was no improvement in altering compliance in the Dysport 30 group compared to placebo.

5.     Dysport 30 was more effective compared to Placebo 30 at decreasing maximum detrusor pressure and increasing maximum cystometric capacity at 14, 42, and 84d follow-ups (p<0.05).

6.     Dysport 30 was more effective compared to placebo at increasing reflex volume at first detrusor contraction, but only at 14 and 42d follow-up time points (p<0.05).

Huang et al. 2016b

China

RCT

PEDro=8

N=80

 

Population: UI; Experimental; Mean age: 31.85 yr; Gender: males=24, females=17; ASIA classification: A=29, B=11, C=1; Mean time post-injury: 16.81 mo; Control: Mean age: 33.43 yr; Gender: males=26, females=13; ASIA classification: A=28, B=8, C=3; Mean time post-injury: 17.29 mo.

Treatment: Experimental individuals received two injections of Botox (OnaBTX) simultaneously, one into the bladder wall (24 mL, 160U) and one into the bladder trigone (6 mL, 40 U). Control individuals only received the bladder wall injection (24 mL, 160 U). Follow-up took place at 4 wk and 12 wk post-injection.

Outcome Measures: Treatment success, Incontinence-Specific-Quality-of-Life Instrument (I-QoL), vesicoureteral reflux (VUR), bladder compliance (BC), detrusor leak point pressure (DLPP), UI episodes per 24 h period, complete dryness, voiding volume with combination of catheterization volume and voided volume.

1.     7 subjects experienced mild hematuria and 5 experienced bladder discomfort; none required medication or surgical intervention.

2.     No individuals developed VUR after injection. Experimental group had a increase in bladder compliance at 12 wk (p=0.04) and a greater improvement in DLPP from baseline to 12 wk (p=0.01).

3.     Between-subjects measures showed that the experimental group had significantly higher I-QoL scores at both 4 wk (p=0.04) and 12 wk (p=0.02). Similarly, experimental individuals saw a significant increase in complete dryness (4 wk {p=0.03}, 12 wk {p=0.01}), and voiding volume (4 wk {p=0.04}, 12 wk {p=0.01}) post-injection. UI episodes significantly increased for those in the experimental group at both 4 wk (p=0.03), and at 12 wk (p=0.01), but decreased overall compared to baselines.

Hui et al. 2016

China

RCT

PEDro=7

Ninital=96; Nfinal=91

Population: SCI NDO, UI; Experimental group: Mean age: 29.83 yr; Gender: males=28, females=19; ASIA classification, A=27, B=12, C=8; Mean time post-injury: 20.04 mo. Control group: Mean age: 28.46 yr: Gender: males=23, females 21; ASIA classification: A=29, B=10, C=5; Mean time post-injury: 19.43 mo.

Treatment: Experimental individuals (n=47) received botulinum toxin A (BTX-A) injections, 160 U into the detrusor and a second intratrigonal one of 40 U. Control individuals (n=44) only received a 200 U injection of BTX-A into the detrusor. Follow-up data was collected at 4 wk and 12 wk.

Outcome Measures: Incidence of vesicoureteral reflux (VUR), maximum detrusor pressure during first involuntary detrusor contraction (PdetmaxIDC), volume at first involuntary detrusor contraction (VFIDC), duration of first DO, incidence of DO, Incontinence-Specific-Quality-of-Life Instrument (I-QoL), UI episodes in 24 hrs, complete dryness.

1.     No individuals had an occurrence of VUR post-injection. Individuals in the control group demonstrated a significantly stronger decrease for PdetmaxIDC (p=0.04), VFIDC (p=0.02), duration of first detrusor contraction (p=0.03), and number of individuals with involuntary detrusor contraction (p=0.02).

2.     The experimental group did not show as dramatic a decrease in secondary urodynamic parameters as the control group on measures of UI episodes per day (4 wk {p=0.03}, 12 wk {p=0.01}), voiding volume (4 wk {p=0.04}, 12 wk {p=0.02}), and I-QoL score (4 wk {p=0.02}, 12 wk {p=0.01}). Individuals in the experimental group reported higher rates of complete dryness compared to those in the control group both at 4 wk (p=0.03) and 12 wk (p=0.01).

Chen et al. 2014

Taiwan

RCT

PEDro=5

N=72

Population: Urinary incontinence; Mean age: 41.5 yr; Gender: males=43, females=29; Level of injury: cervical=31, thoracic=39, lumbar=2; ASIA classification: A=56, B=4, C=6, D=5, E=1; Mean time post-injury: 8.7 yr.

Treatment: Individuals were randomly assigned to receive two injections of either 200U or 300U Onabotulinumtoxin-A (OnaBTX) into the detrusor 6 mo apart.

Outcome Measures: Quality of life (Urogential Distress Inventory (UDI-6), Incontinence Impact Questionnaire (IIQ-7), International Prostatic Symptom Score questionnaire); cystometric bladder capacity (CBC), maximum flow rate (Qmax), post-void residual (PVR) volume, voided volume, detrusor pressure at maximum flow rate (Pdet.Qmax)

1.     Incontinence severity did not significantly decrease within or between groups over time or as a result of treatment. There were no significant changes on the quality of life score on individual questionnaires or the overall quality of life score within or between groups.

2.     Compared to the 300-U group, the 200-U group saw a significant decrease in Qmax (p=0.02) and Volume (p=0.028) from baseline to 12 mo. Both groups showed similar significant increases in CBC (p<0.05) and PVR volume (p<0.05) when comparing baseline to 12 mo. Both groups showed a similar significant decrease in Pdet.Qmax (p<0.05) from baseline to 12 mo. There were no significant changes in compliance within or between groups.

Krhut et al. 2012

Czech Republic

RCT

PEDro=5

N=32

Population: SCI with NDO. Mean age: 32.1 yr (20-55); Gender: males=26, females=6; Level of injury: Cervical=16, Thoracic=14, Lumbar=2; Neurological level: ASIA A=24, B=6, C=2; Time post-injury: Group A=16 to 154 mo (average=58.8), Group B=11 to 276 mo (average=60.7).

Intervention: Individuals received either 300U onaBTX (30 injections =1 mL each) into the intradetrusor (Group A) or suburothelial (Group B).

Outcome Measures: Frequency of urinary catheterization, incontinence episodes, Catheterized volume (Void Volume (VV)), Cystometric capacity (CBC), Volume at first involuntary detrusor contraction (Vol at FC), Maximal detrussor pressure during filling (pdetF), Detrusor compliance. Urodynamics measured at baseline and 3 mo post-treatment.

1.     The number of individuals requesting repeat treatment greater in Group A (64%) than Group B (89%).

2.     The following parameters decreased post-intervention in both groups, although there was no significant different between groups:  bladder catheterizations (p=0.331), incontinence episodes (p=0.492), and PdetF (p=0.568).

3.     The following parameters increased post-intervention in both groups, although there was no significant different between groups:  VV (p=0.254), CBC (p=0.314), and Vo at FC (p=0.482).

4.     Detrusor compliance increased in both groups but significantly greater in group A compared to group B (p=0.021).

5.     One individual from Group A had a treatment-related adverse effect (loss of muscle strength for 7 d) which resolved completely.

Herschorn et al. 2011

Canada

RCT

PEDro=10

N=57

Population: Mean age: 42.8 yr (range 32-50); Gender: males=34, females=23. All individuals had NDO secondary to SCI (N=38) or MS (N=19).

Intervention: Individuals received 1 intradetrusor injection cycle (30 injection sites sparing trigone) of 300U (N=28) of onaBTX (diluted in 30ml of saline), or saline placebo (N=29). Baseline – 3-d voiding diary and multichannel urodynamics. Wk 1, 3 and 4 – telephone followups. wk 6, 24 and 36.

Outcome Measures: Urinary incontinence (UI), detrusor volume at filling, maximum cystometric capacity (CBC), complete continence, maximum detrusor pressure during filling; (PdetF), adverse events.

1.     Of the 52 subjects who completed to wk 36, 24 individuals per group (N=48) received open label onaBTx and completed the study.

2.     The following parameters significantly decreased more in the treatment group than the control group: incontinence episodes (p<0.001 at 6, 24, 36 wk), and PdetF (6, 24 wk p<0.001; 36 wk p=0.001).

3.     The following parameters significantly decreased more in the treatment group than the control group: detrusor volume at filling (6 wk p=0.002, 24 wk p=0.023), CBC (6wk p=0.002, 24 wk p=0.031).

4.     Compared to the control group at wk 6, the treatment group had significantly less incontinence episodes when asleep (p<0.05) or when physically active or exercising (p<0.01).

5.     Complete continence was achieved by wk 24 for 10.7% in the treatment group and 0% in the control group.

6.     At week 6, 14/21 (67%) of individuals in the onaBTx group resumed antimuscarinics, versus 17/18 (94%) in the placebo group resp. (p=0.0489)

7.     Adverse events included urinary tract infection, muscle weakness, mild arm weakness, difficult transfers; one individual had an increase in detrusor pressure of >102 cmH2O.

Abdel-Meguid 2010

Saudia Arabia

RCT

PEDro=10

N=36

Population: SCI individuals: Mean age: 25 yr (range 20-37); Gender: males=34, females=2; Time post-injury: 31 mo (range 10 mo-11 yr).

Intervention: Individuals were randomized to receive either 300 U onaBTX injections into the detrusor (detrusor arm, n=18) or 200 U onaBTX injextions into the detrusor plus 100 U onaBTX into the trigone (combined arm, n=18).

Outcome Measures: Incontinence episodes, complete dryness, maximum detrusor pressure, maximum cystometric capacity, reflex volume, vesicoureteral reflux, and adverse events.

1.     All parameters within both treatment groups improved significantly compared to baseline.

2.     Between group analysis showed greater improvements for the combined group than detrusor only group for the following parameters: incontinence reduction, complete dryness, and reflex volume (p<0.001 for all).

3.     There were no significant differences between groups in cystometric capacity (p<0.22) or maximum detrusor pressure (p<0.21).

4.     No individuals showed new or upgraded vesicoureteral reflux or reported significant adverse events.

Ehren et al. 2007

Sweden

RCT

PEDro=6

N=31

Population: Mean age: 36 yr; Gender: males=17, females=14.

Treatment: Participants were randomly selected to receive intravesical injections of either 500 U of aboBTX or placebo. Participants not experiencing any therapeutic effects of the injection were allowed to use a maximum of 2 tablets of tolterodine daily.

Outcome Measures: Intake of tolterodine, bladder capacity, maximum detrusor pressure, leakage d. Individuals were followed for 26 wk.

1.     Individuals in the placebo group had a significantly higher intake of tolterodine tablets than the aboBTX group (p=0.003).

2.     Cystometric bladder capacity was significantly higher in the aboBTX group than the placebo group at 6 (p<0.001) and 12 wk (p=0.026); but not at 26 wk.

3.     Maximum bladder pressure was significantly lower in the aboBTX group compared to the placebo group (p<0.01).

4.     aboBTX group had significantly less leakage than the placebo group (p<0.01).

5.     No muscular weakness was reported.

Schurch et al. 2007

Switzerland

RCT

PEDro=5

N=59

Population: Individuals with urinary incontinence caused by neurogenic detrusor overactivity >6 weeks with SCI (n=53) or multiple sclerosis (n=6); individuals were aged>18 yr.

Intervention: Individuals were randomized to receive single dose intradetrusor injections of onaBTX  at 1) 200U, or 2) 300U, or 3) a placebo.

Outcome Measures: Incontinence Quality of Life questionnaire (I-QoL).

1.     I-QoL scores were similar for all three treatment groups at baseline; post-treatment, median total I-QoL scores improved in both onaBTx groups but not in the placebo group (p<0.05 for both)

2.     Twice as many onaBTX recipients compared to placebo recipients achieved a minimally important difference in total I-QoL score at 2,6,12 and 24 wk.

Schurch et al. 2005

USA

RCT

PEDro=8

N=59

Population: Mean age: 41 yr; Gender: males=36, females=23; Severity of injury: AIS: A=33, B=10, C=5, D=4, E=1.

Intervention: Participants were randomized in a 1:1:1 ratio into one of three groups: 300 U onaBTX, 200 U onaBTX, and placebo. Participants received a single dose into the detrusor.

Outcome Measures: Incontinence episodes, maximum cystometric capacity, reflex detrusor volume and maximum detrusor pressure. Subjects were followed up at 2, 6, 12, 18, and 24 wk.

1.     Significant decrease was seen in:

·     Incontinence episodes for each onaBTX group (p<0.05).

·     Maximum detrusor pressure for each onaBTX group (p<0.023).

2.     Significant increase was seen in:

·     Mean maximum cystometric capacity in each onaBTX group (p<0.020).

·     Mean reflex detrusor volume at 6 wk in the 300 U onaBTX group and at 24 wk in the 200 U onaBTX group (p<0.021).

Chen et al. 2018

Taiwan

Prospective Controlled Trial

N=36

Population: Experimental group: SCI with urinary incontinence +/-difficulty emptying bladder, +/- intermittent catheterization  Mean age=42.7±13.1yr; males=17; females=9; Etiology: complete SCI=20; incomplete SCI=6;

Control group: Non-SCI with stress urinary incontinence without urgency frequency Mean age=52.4±10.5 yr; Males=0; females=10; Etiology: Stress urinary incontinence=10);

Intervention: Individuals in both groups received 200 U onabotulinumtoxinA injections diluted in 20mL of saline, injected into 40 sites in the detrusor. A urethral catheter was inserted and removed the next morning. Individuals also received broad-spectrum antibiotics for 3d post-intervention.

Outcome Measures: Urodynamic parameters including: first sensation of filling (FSF); full sensation (FS); urge sensation (US); compliance; cystometric capacity (CBC), detrusor pressure at Qmax (Pdet); Qmax; post-void residual volume (PVR); voided volume (VV).

Urothelial dysfunction parameters and sensory protein expression including: E-cadherin; zonula occludens (ZO-1); Mast cells; terminal deoxynuceotidyl transferase time-point within spinal cord injured individuals (TUNEL); muscarinic receptor 2 (M2); muscarinic receptor 3 (M3); β3-adrenoreceptor (β3-AR); purinergic receptor (P2X3); inducible nitric oxide (iNOS); epithelial nitric oxide (eNOS). Outcome measures were assessed at baseline, 3mo follow-up, and 6mo follow-up.

1.     There were no significant differences in FSF, US, compliance, Qmax, and VV when comparing the experimental group with the control at all time points (p>0.05).

2.     Pdet decreased and CBC and PVR increased significantly 3mo post- onabotulinumtoxinA injection, bu these effects faded at 6mo (p<0.05).

3.     TUNEL increased significantly in SCI individuals when comparing 3mo to 6mo follow-up post- onabotulinumtoxinA injection (p=0.047).

4.     E-cadherin and ZO-1 decreased significantly at 3mo compared to baseline in the SCI individuals (p=0.001; p=0.027). The remaining urothelial dysfunction parameters and sensory protein expression did not change significantly in individuals with SCI (p>0.05).

Chen et al. 2016a

Taiwan

Prospective Controlled Trial

N=20

Population: SCI with NDO; Mean age: 48.2 yr; Gender: males=11, females=9; Level of injury: cervical=7, thoracic=11, lumbar=2. Control: Mean age; 54.4 yr; Gender: female=10.

Treatment: Individuals with NDO and that were refractory to anti-muscarinic treatment received 4 injections every 6 mo of 10 mL OnabotulinumtoxinA (OnaBTX) into the detrusor. Controls received no intervention.

Outcome Measures: Treatment outcome, cystometric capacity (CBC), post-void residual (PVR) volume, maximum flow rate (Qmax), detrusor pressure (Pdet. Qmax), volume voided, compliance. Histological measures include E-cadherin and ZO-1 expression, mast cell activation, urothelial cell apoptosis (TUNEL).

1.     Satisfactory dryness was reported by 60% of individuals, no severe adverse events occurred after OnaBTX injection, and five individuals had slight hematuria which spontaneously resolved without intervention.

2.     CBC and PVR significantly increased six mo after each injection. Qmax, Pdet. Qmax, and volume all significantly decreased with treatment. Compliance was non-significant.

3.     At baseline, expression of E-cadherin and ZO-1 was significantly lower in SCI individuals compared to controls (p<0.01). SCI individuals showed a significant increase in urothelial cell apoptosis compared to controls at baseline (p<0.047).

4.     Six mo after each injection E-cadherin and ZO-1 expression significantly improved compared to baseline, E-cadherin expression was significantly higher at the third injection (p=0.004) compared to baseline. There were no significant differences in mast cell activity or TUNEL expression with treatment compared to baseline.

Chen et al. 2016b

Taiwan

Prospective Controlled

N=26

Population: Experimental, NDO; Mean age: 42.7 yr; Gender: males=17, females=9; Level of injury: cervical=12, thoracic=14; Control, urinary stress incontinence; Mean age: 51.4 yr; Gender: females=10.

Treatment: Participants with NDO received a 10mL injection of Onabotulinumtoxin-A (OnaBTX) into the detrusor muscle. Participants were evaluated at 3 mo and 6 mo after treatment. Controls received no intervention.

Outcome Measures: Treatment success, cystometric bladder capacity (CBC), detrusor pressure, maximum flow (Qmax), post-void residual (PVR), compliance, detrusor overactivity, glomerular filtration rate, and serum creatinine. Histological measures include E-cadherin and ZO-1 expression, mast cell activation, and urothelial cell apoptosis (TUNEL).

1.     No severe side effects were reported as a result of OnaBTX injection, 5 participants had slight hematuria which spontaneously resolved without intervention, 6 participants developed UTIs and 7 developed urinary retention.

2.     CBC, Qmax, and glomerular filtrate did not significantly change with treatment. Detrusor pressure significantly increased with treatment at 3 mo only (p<0.001). PVR significantly increased at both 3 mo (p<0.001) and 6 mo (p=0.033), compliance demonstrated the same trend at both 3 mo (p=0.017), and 6 mo (p=0.003), and serum creatinine significantly increased after 6 mo only (p=0.007).

3.      E-cadherin was significantly lower in participants at baseline compared to controls, post treatment, there was a significant increase both compared to baseline and controls at 3 mo (p=0.07) and 6 mo (p=0.07). ZO-1 expression was significantly lower in participants compared to controls at baseline and significantly increased compared to baseline at 3 mo (p=0.05), but remained significantly lower than controls over time. Mast cell count was significantly higher in individuals compared to controls at all times and there were no significant changes in mast cell activation as a result of treatment. TUNEL expression was significantly higher in participants compared to controls at all times and did not significantly change post-treatment.

Anquetil et al. 2016

France

Cohort

N=30

 

Population: Detrusor overactivity; Mean age: 41.9 yr; Gender: males=16, females=14; Level of injury: paraplegia=12, tetraplegia=18; Severity of injury: complete=23, incomplete=7; Mean time post-injury: 16.57 yr.

Treatment: Participants had received either at least two successive intra detrusor botulinum therapy injections (BTX) or augmentation enterocystoplasty (AC).

Outcome Measures: Method of bladder drainage, urinary incontinence, complications, maximum detrusor pressure, low compliance, maximum cystometric bladder capacity, Qualiveen-30.

1.     In the BTX group, 12 used clean intermittent self-catheterization, two used clean intermittent catheterization, and zero used indwelling catheterization, while in the AC group, 14 used clean intermittent self-catheterization, one used clean intermittent catheterization, and one used indwelling catheterization.

2.     Urinary incontinence occurred more frequently in BTX than AC (p=0.0187).

3.     Four AC participants had postoperative complications while there were no complications for BTX participants. No significant differences between groups were observed in terms of urinary lower tract infections.

4.     Two participants had a high maximum detrusor pressure and one participant had low compliance in the BTX group compared to none in the AC group.

5.     Maximum cystometric bladder capacity in BTX group was 418 mL compared to 550 mL in AC group.

6.     The mean Qualiveen-30 score was significantly higher in BTX group than in AC group (p=0.037).

Chartier-Kastler et al. 2016

USA

Case Control

N=435

Population: SCI (n=190), MS (n=245).NDO; Mean age: 40.7 yr; Gender: males=67, females=30; MS (n=245).

Treatment: Participants received either a 200 U onabotulinumtoxin (BTX) injection into the detrusor, or a placebo injection. Six wk after injection follow-up data was collected.

Outcome Measures: Treatment goals (self-identified) such as ‘be dry’, reduce incontinence’ and ‘improve bladder control’, proportion of participants who achieved their goals, and goal achievement by etiology and use of catheterization.

1.     Overall, 62% of participants in the OnaBTX group achieved their goals compared to only 17% in the placebo group.

2.     Based on etiology, participants with SCI and MS both reported significantly greater goal achievement with BTX treatment compared to placebo (p<0.001).

3.     Regardless of catheterization use at baseline, goal achievement was still significantly higher in participants in the BTX group compared to those in the placebo group (p<0.001).

Grosse et al. 2009

Germany

Case Control

N=56

NAboBTx=28

NOnaBTx=28

Population: AboBTx group (n=28): Mean age: 36.8yr; Gender: males=19, females=9; Type of injury: SCI=23, myelomeningocele=3, MS=2; Level of injury: paraplegia=24, tetraplegia=4; Severity of injury: incomplete=13, complete=15; Bladder management type: intermittent catheter=25, reflex voiding=3;OnaBTx group (n=28): Mean age: 37.4yr; Gender: males=22, females=6; Type of injury: SCI=24, myelomeningocele=1, MS=1, central trauma=2; Level of injury: paraplegia=24, tetraplegia=4; Severity of injury: incomplete=12, complete=16; Bladder management type: intermittent catheter=26, reflex voiding=1, indwelling catheter=1.

Intervention: Participants were retrospectively divided into two groups: aboBTx group included those who had been previously been treated with aboBTx (500 IU, 750 IU, or 1000 IU); onaBTx group consisted of participants previously treated with onaBTx (300 IU, 200 IU or 400 IU). Both types of injections were into the detrusor. The efficacy of both treatments was accessed.

Outcome Measures: Continence volume, medication use, dosage change, repeat injections

1.     The aboBTx (469mL) and onaBTx (396mL) groups only differed significantly at 3 mo for the continence volume, p=0.015.

2.     No significant difference was seen in individuals’ medication use or dosage between the two groups.

3.     21 individuals in the aboBTx group had repeat injects when their condition relapsed at about 13 months, while 26 onaBTx group individuals required a repeat injection at an average of 10 months.

4.     Treatment failure (reinjection in less than 3 mo) was seen in 5 aboBTx group individuals.

Huang et al. 2016a

China

Pre-Post

N=59

Population: DO and DESD; Mean age: 39.1 yr; Level of injury: cervical=28, thoracic=25, lumbar=6; ASIA classification: A=42, B=14, C=3; Mean time post-injury: 11.74 mo.

Treatment: Participants received 200 U Botox (OnaBTX) injections in two areas{, 30 mL into the detrusor muscle, and 4 mL into the external urethral sphincter with a follow-up of 12 wk post-injection.

Outcome Measures: Treatment success, Incontinence-Specific Quality-of-Life Instrument (I-QoL), maximum detrusor pressure at first DO and DESD (PdetmaxDO-DESD), volume at first DO and DESD (V DO-DESD), maximum urethral closure pressure (MUCP), duration of first DO and DESD, voiding volume, urinary incontinence, and complete dryness.

1.     Compared to baseline I-QoL scores significantly increased from 32.06 to 62.45 at 12 wk follow-up (p<0.05). Overall participants reported satisfaction with the treatment, reporting less autonomic dysreflexia, decreased UI, less symptomatic UTI and more complete dryness.

2.     Significant decreases were seen in Pdetmax DO_DESD (p<0.05), MUCP (p<0.05), and duration of first DO and DESD (p<0.05) post-injection at 12 wk.

3.     Voiding volume consistently increased from 2 wk to 12 wk post-injection (p<0.05), as did the occurrence of complete dryness (p<0.05). Urinary infections significantly decreased with injection from 2 wk to 12 wk (p<0.05).

Fougere et al. 2016

Canada

Pre-Post

N=17

Population: NDO; Mean age: 44 yr; Gender: males=12, females=5; Level of injury: cervical=11, thoracic=6; ASIA classification: A=9, B=5, C=3; Mean time post-injury: 21 yr.

Treatment: All participants had confirmed anticholinergic drug resistance and received one cycle of 200 U Onabotulinumtoxin-A (OnaBTX) injections into the detrusor. Baseline, post-injection, and one month post-injection data was examined.

Outcome Measures: Quality of life (Health-Related Quality of Life Questionnaire, Incontinence Quality of Life Questionnaire), hemodynamic measures (systolic blood pressure (SBP) and heart rate (HR)) during urodynamic studies (first urge to perform clean intermittent catheterization and maximum volume infused).

1.     All subsections of the HR-QoL (p<0.001) and the I-QoL (p=0.001) questionnaire showed significant improvement post-treatment, overall bladder function was improved post-injection.

2.     SBP at first urge to perform CIC (p<0.001) and at maximum volume infusion (p<0.001) and overall SBP (p=0.001) all significantly decreased with botox treatment. Treatment resulted in a 59% decrease in the incidence of autonomic dysreflexia (AD), as well as a 35% decrease in associated symptoms such as goosebumps, chills/tingles, flushing or headache. Following injection both maximum SBP and ∆SBP significantly decreased during bladder related events. No significant changes in HR were seen when examining the effects of treatment on urodynamic parameters.

Population: Experimental; NDO; Mean age: 46 yr; Gender: males=7, females=5. ASIA classification: A=6, C=2, D=1; Injury etiology: SCI=9, MS=2, Meningomyelocele=1. Control; Mean age: 46 yr; Gender: males=7, females=5.

Treatment: NDO individuals (n=12) were given a 300 U intradetrusor injection of onabotulinumtoxinA, (OnaBTX) and compared to age-matched healthy controls (n=12)

Outcome Measures: ECG measures: r-waves, RR intervals and discrete event series (DES), power spectra from DES integral very low frequency (VLF), low frequency (LF), high frequency (HF) ranges, and power. Measures were calculated at baseline, and 3 subsequent visits post-injection.

1.     At baseline and 1st visit there were no significant differences between the experimental group and control group. On the 3rd visit, the experimental group had significantly higher power (p=0.046) as well as a higher resting heart rate (p=0.004) than controls at the 4th visit. These were the only statistically significant outcomes.
Peyronnet et al. 2016a

France

Pre-Post

N=26

Population: NDO, failed first abobotulinum toxin injection; Mean age: 40.8 yr; Gender: males=11, females=15; ASIA classification: A=9, B=2, C=1, D=1, E=1; Injury etiology: SCI=14, MS=9, SB=2, Myelitis=1; Mean time from onset: 9.4 yr.

Treatment: All participants received 2 series of injections, one dose of 300 U of Botox (OnaBTX), and one dose of 750 U of Dysport (abobotulinum toxin) into the detrusor muscle. Participants were evaluated at baseline and 6 wk after injection.

Outcome Measures: Mean number of micturition per day, mean number of UI episodes per day, UI between catheterizations, voided volume, volume at first involuntary detrusor contraction, maximum detrusor pressure, maximum cystometric capacity, detrusor over activity.

1.     There was a significant reduction in mean number of micturition per day (p<0.001), as well as mean UI episodes per day (p<0.001) from baseline to 6 wk post-injection.

2.     The number of participants experiencing incontinence between catheterizations also significantly decreased with treatment (p<0.001).

3.     Urodynamic parameters of voided volume (p<0.001) as well as maximum cystometric capacity (p=0.048) significantly increased with treatment, while max detrusor pressure (p=0.048) significantly decreased with treatment from baseline to 6 wk post-injection.

4.     Detrusor overactivity was seen to be eliminated in approximately have of the participant population (p<0.001) as a result of treatment.

Chen & Kuo 2015

Taiwan

Pre-Post

N=59

Population: NDO, refractory to anticholinergics; Mean age: 42.1 yr; Gender: males=38, females=21; Level of injury: cervical=26, thoracic=28, lumbar=5; ASIA classification: A=39, B=9, C=5, D=5, E=1; Mean time post-injury: 8.7 yr.

Treatment: 4 injection cycle every 6 mo of 20 mL of OnabotulinumtoxinA (OnaBTX) into the bladder wall, with follow-up every 3 mo (Phase I), with the option of progressing to two more injection cycles 6 months apart (Phase II).

Outcome Measures: Treatment success, cystometric bladder capacity (CBC), maximum flow rate (Qmax), post-voiding residual volume (PVR), voided volume, involuntary detrusor contractions (IDC), voiding detrusor pressure at Qmax (Pdet. Qmax), lower urinary tract symptoms (using Urogenital Distress Inventory short form).

1.     After the first OnaBTX injection 17 of 52 participants did not continue treatment. Twenty participants reported failure to one or repeated injections, 10 had improvement fluctuate after one or repeated injections, and 10 reported no significant improvement.

2.     CBC and PVR volumes significantly increased with treatment, Pdet. Qmax had a significant decrease. IDC decreased at 3mo and increased slightly at 6 mo. Qmax and voided volume, decreased with treatment both at 3 mo and 6 mo.

3.     Lower urinary tract symptoms decreased with treatment overall. Moderate and severe incontinence was noted in 74.6% of participants at baseline, which decreased to 25.9% and 44.4% at 3 mo and 6 mo respectively after the fourth injection. However, the overall therapeutic effect of the treatment was seen to decrease after the fourth injection.

Sengoku et al. 2015

Japan

Pre-Post

N=19

Population: SCI with NDO; Gender: males=13, females=6.

Treatment: All participants received 200 U of onabotulinutoxinA (OnaBTX) injected in to the sub-epithelial bladder. Evaluation took place at baseline and one month post-injection.

Outcome Measures: UI frequency, proportion of continence cases, frequency of clean intermittent catheterization, catheterized volume, International Consultation on Incontinence Questionnaire (ICIQ), maximum cystometric capacity, bladder compliance, maximum pressure of DO.

1.     UI frequency (p=0.004), and frequency of CIC (p=0.014) significantly decreased with treatment, while proportion of continence cases (p<0.001) and catheterized volume (p=0.003) increased with treatment.

2.     ICIQ scores significantly decreased on both parameters of overall score (p<0.001) and interference with everyday life (p<0.001).

3.     All cystometric variables significantly changed as a result of treatment. MCC (p<0.001) and bladder compliance (p=0.031) significantly increased, while incidence of DO cases (p=0.016) and max pressure of DO (p=0.002) significantly decreased.

Ge et al. 2015

China

Pre-Post

N=24

Population: SCI with NDO Mean age: 42.6 yr; Gender: males=19, females=5; Level of injury: cervical=14, thoracic=4, lumbar=6; ASIA classification: A=13, B=3, C=5, D=3.

Treatment: All participants received an injection of 300 IU Botulinum toxin type A (BXT-A) into the detrusor muscle and were followed-up at 2, 6, 12, 18 and 24 weeks.

Outcome Measures: Urodynamic parameters included maximum cystometric capacity (MCC), reflex detrusor volume (RDV), and maximum detrusor pressure during bladder contraction (MDP) (measures taken at 2, 6, and 24 weeks). The Incontinence Quality of Life Questionnaire (I-QOL) was also used to asses quality of life along with self-reported measures of involuntary urine loss frequency, catheterization frequency, and % of individuals completely dry over 24 h.

1.     MCC significantly increased with injection at 2 wk (p=0.001), 6 wk (p=0.001), and 24 w (p=0.002) compared to baseline. Both RDV and MDP significantly increased with treatment over 2 wk (p=0.001, p=0.034), 6 wk (p<0.001, p=0.029), and 24 wk (p<0.001, p=0.036) compared to baseline.

2.     I-QOL scores increased from 19.7 to 80.3 two wk after injection (p=0.001), indicating that individuals were satisfied/very satisfied with the treatment results. Satisfaction level was correlated to fewer leakages per day. Involuntary urine loss frequency significantly decreased at 2 wk (p=0.017) and was still significantly lower at 24 wk (p=0.02) compared to baseline. Catheterization frequency also decreased at 2 wk (p=0.001) and remained significantly lower than baseline at 24 wk (p=0.006). Percentage of participants completely dry increased from 0% at baseline to 82% at 2 wk and 68% at 24 wk.

Al Taweel et al. 2015

Saudi Arabia

Pre-Post

N=103

Population: Drug-resistant NDO; Mean age: 29 yr; Gender: males=71, females=32; Level of injury: cervical=10, thoracic=42, lumbar=51.

Treatment: Participants received one series of OnabotulinumtoxinA (OnaBTX) injections, totalling 30ml into detrusor muscle.

Outcome Measures: Frequency of urge urinary incontinence, maximum cystometric bladder capacity (MCBS), reflex volume (RV), maximum detrusor pressure (MDP), side-effects, antimuscarinic drug consumption, quality of life measured as a visual analogue scale (VAS).

1.     Compared to baseline, there was a significant reduction in the number of incontinence episodes after treatment (diary recordings).

2.     All urodynamic bladder parameters significantly increased post treatment, MCBS (p<0.001), RV (p<0.001), and MDP (p<0.001).

3.     Of the 103 participants, 14 showed poor clinical improvement (nonresponders), 20 participants experienced mild hematuria, and 15 participants experienced urinary tract infections.

4.     Before treatment, 89 of 103 participants used anticholinergic drugs. After treatment, 55 remained without anticholinergics. Twenty more were able to reduce their daily requirements.

5.     A significant improvement in participant satisfaction was found after treatment, with a mean improvement of three points (VAS). Mean duration of symptomatic improvement was 8 mo, with earliest recurrence of clinical symptoms at 10 wk.

Alvares et al. 2014

Brazil

Pre-Post

N=34

Population: SCI with incontinence due to NDO refractory to intravesical oxybutynin doses greater or equal than 40mg Mean age: 31.2 yr; Gender: males=23, females=11; Level of injury: paraplegia=28, tetraplegia=6; Injury etiology: traumatic=25, non-traumatic=9; Mean time post-injury: 5.9 yr.

Treatment: Received one series of Botulinum toxin A injections totalling 30ml into the detrusor muscle.

Outcome Measures: Treatment success, reflex volume (RV), maximum detrusor pressure (MDP), bladder compliance, maximum cystometric capacity (MCC), presence of diverticula, anticholinergic drug use.

1.     After treatment, 24 participants remained continent for more than 4 mo and were considered successful.

2.     At 4 mo post-treatment, RV was significantly increased (p<0.001), MCC was significantly increased (p<0.001), and MDP was significantly decreased (p<0.001).

3.     Bladder compliance did not significantly change with treatment.

4.     Pre-treatment, 24 participants had no diverticula, eight had between 1 and 10, and two had greater than 10. No correlation was found between the presence of diverticula and response to treatment.

5.     After four mo follow-up, 20 participants had reduced their dose of anticholinergics, 5 had discontinued use, and 9 had not changed dose.

Chen & Kuo 2013

Taiwan

Pre-Post

N=59

Population: SCI participants with neurogenic detrusor overactivity and urinary incontinence: Mean age: 42.1 yr (range 22-74); Gender: males=38, females=21; Mean injury duration: 8.7 yr; Level of injury: cervical (n=26), thoracic (n=28), lumber (n=5); Severity of injury: AIS A=39, B=9, C=5, D=5, E=1.

Intervention: Four repeated injections of 200-U of onaBTx injected at 20 different sites in the bladder wall every 6 mo.

Outcome Measures: Urogenital Distress Inventory 6-item short form (UDI-6).

1.     The overall treatment satisfaction rate was 59.3% (35/59 participants), the failure rate was 33.9% (20/59 participants), and the discontinuation rate was 6.8% (4/59 participants).

2.     The rate of dryness and mild incontinence as measured by UDI-6 scores improved from 25.4% at baseline to 74% at 3 mo after the fourth injection.

Kuo 2013

Taiwan

Pre-Post

N=55

Population: Injury etiology: SCI=47, MS=6, myelitis=2; All particpants had detrusor sphincter dyssynergia: urinary incontinence (n=13), difficult urination (n=12), mixed urinary incontinence and difficult urination (n=30).

Intervention: Participants treated with urethral sphincter injection of 100U of BTX-A (n=33) or detrusor injection of 200U of BTX-A (n=22).

Outcome Measures: Urodynamic parameters (cystometric bladder capacity (ml), voiding pressure (cmH2O), maximum flow rate (ml/s), postvoid residual (PVR, ml), Quality of life (QoL) via UDI-6 and IIIQ-7; satisfaction of treatment.

1.     Urodynamic parameters showed significant improvements in both groups; in the urethral BTX-A group, voiding pressure and PVR decreased, but bladder capacity remain unchanged whereas in the detrusor BTX-A group, bladder capacity and PVR increased, while voiding pressure and maximum flow rate decreased and detrusor overactivity disappeared in 50% of the participants.

2.     Satisfaction post-treatment was perceived in 60.6% of the urethral BTX-A group and 77.3% of the detrusor BTX-A group.

3.     For the urethral BTX-A group QoL, there was significant improvements in IIIQ-7 scores, but no significant change in UDI-6 scores whereas for the detrusor BTX-A group both IIIQ-7 and UDI-6 scores showed significant improvement.

4.     The changes of IIIQ-7 and UDI-6 in the detrusor BTX-A group were significantly greater than those in the urethral BTX-A group.

5.     Major causes of dissatisfaction with treatment were increased incontinence grade (n=16, 48.5%) and increased urgency (n=5, 15.2%) for the urethral group and increased PVR (n=11, 50%), and difficulty urinating (n=11, 50%) for the detrusor group.

Hikita et al. 2013

Japan

Pre-Post

N=11

Population: Participants with NDO as a result of SCI or multiple sclerosis: Mean age: 48.8 yr (range 23-75 yr); Gender: males=5, females=6.

Intervention: 300 U intradetrusor onaBTx injections.

Outcome Measures: King’s Health Questionnaire (KHQ); maximum cystometric capacity; bladder compliance; incontinence episodes.

 

1.     There were significant reductions in eight of the nine KHQ scores at the 8 wk follow-up.

2.     The mean maximum cystometric capacity increased significantly in all participants at 8 wk follow-up (p<0.001).

3.     Bladder compliance at maximum cystometric capacity also increased significantly in all participants at 8 weeks from baseline (p<0.001).

4.     The number of incontinence episodes/ d decreased significantly at the 8 wk follow-up (p<0.001).

5.     The treatment stopped working at a mean of 7.15 mo post-treatment.

Chen et al. 2011

Taiwan

Pre-Post

N=38

Population: Individuals with chronic suprasacral SCI with neurogenic detrusor overactivity or detrusor sphincter dyssynergia: Mean age: 40.1 yr (range 20-72); Gender: males=17, females=21; Median duration of SCI: 10.3 yr (range 1-35).

Intervention: 200U of Botulinum Toxin A injected into 40 detrusor sites. A repeat of 300U was given when participants felt the therapeutic effects of the first 200U injection wore off. The time gap between the two injections was 6 mo.

Outcome Measures: Urogenital Distress Inventory 6-item short form (UDI-6) questionnaire; QoL index; detrusor pressure at maximum flow rate (Pdet.Qmax); cystometric bladder capacity; post-void residual

1.     A satisfactory response to treatment was found in 23 participants (60%).

2.     Significant increases were found in UDI-6 scores, QoL, cystometric bladder capacity and post-void residual, post-treatment at 3 and 6 month follow-up.

3.     Pdet.Qmax significantly decreased post-treatment.

4.     Neurogenic detrusor overactivity disappeared in 10 participants (23%) post-treatment.

5.     Participants with a high baseline Pdet.Qmax (>40 cmH2O) had significantly greater reductions in detrusor pressures than participants with a lower baseline Pdet.Qmax post-treatment at 3 and 6 month follow-up (p<0.001, p=0.007).

Chen & Liao 2011

China

Pre-Post

N=108

Population: SCI participants with NDO: Mean age: 40.1 yr (range 16-78); Gender: males=81, females=27; Level of injury: C=29, T=58, L=21; Injury severity: complete=85, incomplete=23.

Intervention: 300 IU of Botulinum Toxin A injected cystoscopically into the detrusor muscle at 30 different sites.

Outcome Measures: Continence, quality of life (QoL), urodynamic parameters (mean cystometric capacity, mean reflux volume, mean voiding pressure).

 

1.     80 out of the total participant population were incontinent pre-treatment, post-treatment 51 (63.75%) became continent. 29 of the remaining incontinent individuals (36.25%) had a reduced degree of urinary incontinence post-treatment.

2.     Pre-treatment 80 participants used anti-cholinergics daily, post-treatment 43 (53.75%) of participants stopped using anticholinergics, while an additional 28 (35%) reduced their daily requirement.

3.     Both mean cystometric capacity and mean reflux volume increased significant (p<0.05).

4.     Mean voiding pressure decreased QoL of life significant increased post-treatment (p<0.001).

Kuo & Liu 2011

Taiwan

Pre-Post

N=33

Population: SCI participants all with detrusor sphincter dyssynergia: Mean age: 37 yr (range 2-23); Level of injury: C=7, T=15, L/S=11; ASIA impairment: A=19, B=10, C=4.

Intervention: Repeated detrusor 200U onaBTX injections repeated every 6 mo up to 4 times.

Outcome Measures: Incontinence grade, mean bladder capacity, mean detrusor pressure, mean glomerular filtration rate (GFR), end-filling intravesical pressure, bladder compliance, frequency of clean intermittent catheterization (IC), Quality of Life (Urogenital Distress Inventory 6-item short form (UDI-6), Incontinence Impact Questionnaire 7-item short form (IIQ-7) and self-assessed QoL indices).

 

1.     30/33 (90.9%) of participants reported improvements in incontinence, whether it was an improvement in their incontinence grade (n=18) or they became completely dry (n=12) following initial and subsequent onaBTX injections.

2.     UDI-6, IQ-7, and QoL indices significantly improved at all-time points, improvements were cumulative and persistent following multiple injections.

3.     Mean bladder capacity increased significantly (207ml to 412ml); mean detrusor pressure decreased significantly (39.8 cmH2O to 20.6 cmH2O) post-treatment (all p<0.05).

4.     Bladder compliance also increased significantly (26.9 versus 40.1, p=0.035).

5.     Frequency of IC decreased from 6.5 to 4.3 times per d (p<0.001) for all participants post-treatment.

6.     A significant reduction in GFR was noted in participants with bladder compliance that increased by<10 cmH2O (p=0.002), and in participants with detrusor pressure<10 cmH2O post-treatment (p=0.036).

Wefer et al. 2010

Germany

Pre-Post

N=214

Population: Individuals with SCI (81%), myelomeningocele (14%), and MS (5%) all with NDO: Mean age: 38 yr; Gender: males=145, females=69.

Intervention: Intravesical botulinum toxin A

Outcome Measures: Maximum detrusor pressure, maximum cystometric capacity, detrusor compliance, incontinence episodes, urinary tract infections, incontinence aids

1.     The following urodynamic parameters increased significantly following treatment: maximum detrusor pressure (p=0.004), maximum cystometric capacity (p=0.002), and detrusor compliance (p=0.0001).

2.     The following decreased significantly post-treatment compared with baseline: urinary tract infections (68%-28%, p<0.05), incontinence episodes (63%-33%, p<0.05), and incontinence aids (58%-28%, p<0.05)

Alvares et al. 2010

Brazil

Pre-Post

N=22

Population: Individuals with SCI all with neurogenic incontinence: Mean age: 33.6 yr (range 13-61); Gender: males=19, females=3; Level of impairment: paraplegic=16, tetraplegic=6.

Intervention: Botulinum-A-Toxin injections into the detrusor, sparing the trigone.

Outcome Measures: maximum cystometric capacity, bladder reflex volume, maximum detrusor pressure, bladder compliance, and continence.

1.     Maximum cystometric capacity (219 ml to 404 ml, p=0.01) and bladder reflex volume (175ml to 312ml, p=0.001) both increased significantly post-treatment.

2.     Bladder compliance (30.6 ml/cm to 22.2 ml/cm, p=0.067) and maximum detrusor pressure (78 cmH2O to 49 cmH2O) both decreased post-treatment.

3.     13 participants (59%) achieved continence, however only 9 participants (41%) remained continent at the 6-months followup.

Giannantoni et al. 2009

Italy

Pre-Post

N=17

Population: SCI, NDO; Mean age: 39.7yr; Gender: Males=11, Female=6; Severity of injury: AIS A=11, B=6; Levels of injury : T1–2=1, T4–5=3, T9–10=2, T11–12=7; C=4

Intervention: Participants who previously received intradetrusor BTX for NDO were followed up after about 6 yr.

Outcome Measures: Number of catheterizations; number of incontinence episodes, UDC first volume, UDC maximum pressure, maximum cystometric capacity, quality of life (QoL), urinary tract infections (UTIs) were measured at baseline, 4 mo, 1 yr, 3 yr and 6 yr follow ups.

1.     A significant decrease was seen in daily incontinence episodes and mean catheterization 4 months post treatment (p<0.001).

2.     Improvement in all outcomes were seen at the 6 yr follow-up:

·     Number of catheterizations/d, p=0.01

·     Number of incontinence episodes/d, p=0.01

·     UDC first volume, p=0.001

·     UDC maximum pressure, p=0.01

·     Maximum cystometric capacity, p=0.001

·     UTIs/yr=0.001

·     Mean QoL index increased significantly at 3 yr and 6 yr follow ups (p<0.001).

Hori et al. 2009

UK

Pre-Post

N=72

Population: Mean age: 45.4 yr; Gender: males=43, females=29

Intervention: Individuals with SCI who received intradetrusor aboBTx injections previously were evaluated for overall treatment satisfaction

Outcome Measures: Satisfaction.

1.     48 participants previously receiving aboBTx injection for NDO remained on the treatment, while 24 discontinued treatment due to its ineffectiveness.

2.     Decrease in dosage from 1000 IU to 750 IU resulted in a halt in episodes of muscular weakness in participants previously presenting.

3.     36-68 participants were satisfied or very satisfied with aboBTx treatments with a mean satisfaction score of 6.2.

4.     Younger participants were more likely to consider a permanent surgical solution than older participants (p=0.02).

Del Popolo et al. 2008

Italy

Pre-Post

N=199

Population: SCI participants with NDO: Mean age: 42.5 yr (range 18-74); Mean follow-up: 48 mo (range 16-91).

Intervention: Repeated intradetrusor injections of aboBTxA at doses of 1000, 750, 500 U.

Outcome measures: Incontinence measured by an incontinence episode frequency (IEF) test, maximum cystometric bladder capacity (MCBC), reflex volume (RV), bladder compliance (BC), number of pads/condoms, antimuscarinic drug consumption, short and long term side-effects, quality of life (QoL) measured with visual analogue scale (VAS).

1.     There was no significant difference in the clinical efficacy duration between treatment doses (p=0.5274).

2.     MCBC, RV, and BC improved significantly after treatment compared with baseline values (p<0.001), and there were no significant changes in these parameters after retreatment (p>0.05).

3.     There was a significant improvement in participant satisfaction and QoL after each retreatment as expressed on the VAS (p<0.001).

4.     There was a significant reduction in IEF scores and pads/condom use in the first 4 weeks after each treatment (p<0.0001).

Kuo 2008

Taiwan

Pre-Post

N=50

Population: Detrusor sphincter dyssynergia or detrusor overactivity from SCI=43, MS=2, transverse myelitis=5. Median age: 43 yr (range 25-67); Gender: male=32, female=18; Injury etiology: SCI=43, MS=2, transverse myelitis=5; all participants had urinary tract dysfunction (destrusor sphincter dyssynergia or detrusor overactivity): Level of injury: cervical (n=7), thoracic (n=28), lumbar (n=8); Median duration of SCI: 4.5 yr (range 2-25 yr).

Intervention: 200 U of onaBTx into the detrusor

Outcome Measures: Postvoid residual volume (PVR); Cystometric capacity; detrusor pressure at maximal flow rate (Pdet Qmax); Quality of life (Urogenital Distress Inventory 6-item short form (UDI-6), Incontinence Impact Questionnaire 7-item short form (IIQ-7)).

1.     78% of particpants reported treatment satisfaction; where decreases in incontinence grade and urgency episodes contributed the most to satisfaction.

2.     Maximal bladder capacity increased significantly after treatment (221ml to 432 ml, p=0.000).

3.     PdetQmax decreased significantly after treatment (43.5cmH20 to 12.6 cmH20).

4.     PVR increased significantly after treatment (121ml to 325ml, p=0.000).

5.     Individuals had significant improvement in QoL after treatment (UDI-6: 11.7 versus 4.1, p=0.01, IIQ-7: 16.3 versus 11.7, p=0.03).

6.     Factors that contributed to dissatisfaction included: increased difficulty with urination and need for catheterization.

Mascarenhas et al. 2008

Brazil

Pre-Post

N=21

Population: Mean age: 35.4 yr (range; 15-78 yr); Gender: male=10, female=11. Injury etiology: SCI=12; viral myelitis=8, MS=1 with neurogenic urinary dysfunction:

Intervention: 300U of onaBTx in the trigone on the antireflux mechanism.

Outcome Measures: Incontinence (vesicoureteral reflex), cystometric capacity, reflex volume, maximum detrusor pressure.

1.     20/21 (95.2%) participants had no vesicoureteral reflex post-treatment (9 (42.8%) remained completely dry, 11 (52.4%) had significant improvement with occasional leaks).

2.     Significant increases from baseline were noted in both cystrometric capacity (271.1ml to 390.1 ml, p=0.002) and reflex volume (241ml to 323.1 ml, p=0.02).

3.     Maximum detrusor pressure was significantly reduced post-treatment (66.1 cmH2O to 38.5 cmH2O, p<0.001).

Reitz et al. 2007

France

Pre-Post

N=20

Population: Median age: 41.1 yr (IQR: 22.2-67.5); Gender: male=13, female=7; Injury etiology: SCI paraplegia=15, tetraplegia=1, non-traumatic SCI=2, MS=2; all individuals had NDO.

Intervention: Five intradetrusor injections of 300 U of onaBTx injected into 30 different sites.

Outcome Measures: Continence, reflex volume, maximum cystometric capacity, maximum detrusor pressure, median compliance.

1.     Continence improved significantly after the first injection and remained consistently improved after repeat injections.

2.     The median reflex volume increased significantly (median values: 200ml to 440-500ml).

3.     The presence of neurogenic detrusor overactivity decreased significantly by 60-75%.

4.     Maximum cystometric capacity increased significantly 2,3-fold.

5.     Maximum detrusor pressure decreased significantly (70 cmH2O to 20 cmH2O).

6.     Median compliance at baseline did not change significantly.

Tow et al. 2007

Singapore

Pre-Post

N=15

Population: Mean age: 49.9 yr; Gender: males=10, females=5; Level of injury: paraplegic=6; tetraplegic=9; Severity of injury: complete=11, incomplete=4; Mean follow-up time=7.1 yr.

Intervention: 300 units of onaBTx diluted in 30mL of normal saline solution. 30 injections of 1 ml each were given intramuscularly into the detrusor, sparing the trigone. Participants were asked to reduce anticholinergic drugs after treatment.

Outcome Measures: Mean number of leakages, maximal catheterizable volume, catheterisation frequency, means reflex volume, mean cystometric bladder capacity, maximal detrusor pressure, and mean duration of contraction. A post-treatment assessment was conducted 6 and 26 weeks after injection and a 3 d voiding diary was kept at 2 weeks and 6 weeks.

1.     Mean number of leakages decreased significantly at 6 and 26 weeks post-injection (p<0.05). Catheterization frequency was significantly reduced 6 weeks post-injections (p=0.029) but not 26 weeks and 39 weeks post-injection.

2.     Maximal catheterized volume increased at 6 weeks (p=0.003), 26 weeks (p=0.006), and 39 weeks (p=0.0296) post injection.

3.     Mean reflex volume improved 6 weeks (p=0.0019) and 26 weeks (p=0.0172) post-injection.

4.     Mean cystometric bladder capacity improved at 6 week post-injection (P=0.00007) and at 26 weeks post-injection (p=0.0117).

5.     Maximal detrusor pressure decreased at 6 weeks (p=0.00007) and 26 weeks (p=0.0117) post-injection.

6.     The duration of contraction showed no significant difference from pre-injection to 6 and 26 weeks post-injection.

Karsenty et al. 2006

France

Pre-Post

N=17

Population: Injury etiology: SCI=16, MS=1, with NDO and incontinence.

Intervention: Repeated injections of 300 U of onaBTx injected into the detrusor muscle at 30 sites.

Outcome Measures: Incontinence episodes, maximal cystometric bladder capacity, reflex volume, maximal detrusor pressure, compliance.

1.     The mean number of injections per participant was 5.4 injections, no systemic side effects were observed after any of the total 91 injections.

2.     The mean number of incontinence episodes/d decreased from 2.6 at baseline to 0 after the first injection, and remained at 0 after the participants’ last injection.

3.     Maximal cystometric bladder capacity increased significantly after the first injection from baseline (mean capacity: 348.8ml to 499.1ml, p<0.0002).

4.     Repeated injections did not induce greater increases in the maximal cystometric bladder capacity than after the first injection (p=0.06).

5.     A significant decrease in maximal detrusor pressure after treatment was noted (75.5cm to 28.8cm, p<0.0001).

6.     The reflex volume increased significantly from baseline after the first injection (205.9ml to 351.2ml, p<0.0005).

7.     No difference in compliance was reported from baseline to the first or last injection.

Patki et al. 2006

UK

Pre-Post

N=37

Population: Mean age: 39.4yr; Gender: males=24, females=14; Level of injury: C=10, T=24, L=3; Severity of injury: complete=25, incomplete=12

Intervention: Individuals with SCI and drug resistant NDO were administered 1000 U aboBTx into the detrusor muscle and followed.

Outcome Measures: Maximum detrusor pressure (MDP), maximum cystometric capacity (MCC), incontinence, QoL.

1.     Significant increase in mean MCC (p<0.001) was seen post aboBTx injection.

2.     MDP decreased significantly post injection (p<0.001).

3.     3 months post injection, 28 participants had no unstable contractions.

4.     26 participants previously incontinent were continent post injection.

5.     QoL questionnaire showed favorable response towards aboBTx injection in 32 participants.

6.     Symptoms began to recur at 8 weeks to 3 months.

Kuo et al. 2006

Taiwan

Pre-Post

N=24

Population: Spinal Cord Lesions (SCL) Mean Age: 38.6yr; Gender: males=11, females=1; CVA Mean Age: 72.4yr; Gender: males=6, females=6

Intervention: Participants with neurogenic detrusor overactivity were administered suburotheral onaBTx injection (200U) and assessed for efficacy.

Outcome Measures: Urinary retention, voiding pressure, bladder capacity, PVR, incontinence.

1.     4 individuals with SCL, without prior history of using ICC, had urinary retention in the 1st post operative week.

2.     Voiding pressure decreased significantly at 1 month compared to baseline in participants with a SCL (p=0.002).

3.     From 1 month to 3 month followup an increase was seen in

·       IDC volume

·       Bladder capacity

·       PVR

4.     From baseline to 3 month follow up:

·       A decrease in incontinence grade was seen

·       An increase in grade of difficulty urinating was seen.

5.     22 participants with SCL reported successful results at 3 months.

Klaphajone et al. 2005

Thailand

Pre-Post

N=10

Population: Mean age: 32.5yr; Gender: males=6, females=4; Level of injury: C=1, T=9; Severity of injury: AIS A=7, B=2, C=1

Intervention: Individuals with SCI and neurogenic detrusor overactivity were injected with 300 U onaBTx into the detrusor muscle.

Outcome Measures: Bladder compliance, functional bladder capacity, volume at first reflex, detrusor contraction, adverse events.

1.     At 6 weeks post injection, significant increase was seen in mean bladder compliance (p=0.012), mean functional bladder capacity (p=0.008) and mean volume at first reflex (p=0.045).

2.     Mean maximum detrusor contraction decreased significantly (p<0.001) 6 weeks post injection.

3.     These effects lasted up till 16 weeks, with levels returning to baseline by week 36.

4.     No adverse effects were seen.

Hajebrahimi et al. 2005

Canada

Pre-Post

N=10

Popluation: Mean age: 41yr; Gender: males=6, females=4; Level of injury: tetraplegia=3, paraplegia=7; Severity of injury: complete=6, incomplete=4: AIS A=6, B=2, C=2.

Intervention: Individuals with SCI and detrusor overactivity who failed to respond to anticholinergic medications were administered 400 U onaBTx injections into the bladder and followed.

Outcome Measures: Reflex capacity, MDP, satisfaction.

1.     An increase of 63.08% was seen in average reflex capacity post injection, p<0.02.

2.     A decrease in MDP of 15.52% was seen post injection however, this was not significant.

3.     Participants reported 90% satisfaction rate.

Bagi & Biering-Soresen 2004

Denmark

Pre-Post

N=15

Population: Mean age: 32 yr (range 24-67); Gender: males=12, females=3; Mean time with SCI=9 yr; Level of injury=C5-L1.

Intervention: 300 IU of Botulinum Toxin A injected cystoscopically into the detrusor muscle, excluding the trigone region.

Outcome Measures: Continence, maximum detrusor pressure, maximum volume at a detrusor pressure of<40 cmH2O, maximum bladder capacity.

1.     13 out of 15 participants (87%) reported continence post-treatment and the volume of leakage was significantly reduced in the 2 incontinent participants.

2.     In all participants; maximum detrusor pressure was significantly reduced (p<0.0005) and the maximum volume at a detrusor pressure of<40 cmH2O was significantly increased (p<0.0005).

3.     Maximum bladder capacity was increased but the increase was not significant compared to baseline.

4.     Participants remained continent post-treatment at a median of 7 months (range 4-12 months).

Schurch et al. 2000 Switzerland

Pre-Post

Ninitial=21;Nfinal=19

 

Population: SCI: Age range 15-59 yr; Gender: males=14, females=7.

Intervention: Outindividual intradetrusor OnaBTx injection under cystoscopic control.

Outcome Measures: Continence level achieved, dose of anticholinergic medication, reflex volume, max detrusor pressure during voiding, detrusor compliance, max cystometric bladder capacity and individual satisfaction.

1.     Significant increase in reflux volume, maximum cystometric bladder capacity (p<0.016).

2.     Increase in post void residual urine volume.

3.     Non-significant voiding pressure change.

4.     At the 6-wk followup complete continence was restored in 17 of 19 cases in which anticholinergic medication was markedly decreased or withdrawn.

5.     11 participants at 16 & 36 wks follow-up continued to show bladder function improvement.

Leitner et al. 2016

Switzerland

Post Test

N=52

Population: NDO; Mean age: 40 yr; Gender: males=24, females=24; Cause of NDO: SCI=32, Spina bifida=8, MS=7, Other=5;

Treatment: All participants received  intradetrusor onabotulinumtoxinA (OnaBTX) before 2011 (300 U) and after 2011 (200 U).

Outcome Measures: Primary outcome measures was eligibility to continue OnaBTX injections. Prerequisites to do so included appropriate clinical and urodynamic effect. Secondary outcome measures were maximum cystometric capacity, compliance, bladder volume, detrusor overactivity, maximum detrusor pressure.

1.     Based on positive clinical and urodynamic effects, 60% of participants continued on with OnaBTX treatment. Nine participants did not continue on with treatment in favor of pursuing other treatment options despite having positive outcomes.

2.     There were no significant differences in secondary urodynamic parameters between participants continuing treatment and those discontinuing treatment.

Gutierrez-Martin et al. 2015

Spain

Case Series

N=70

Population: NDO; Mean age: 39; Gender: males=40, females=30; Level of injury: C1-C8=32, D1-D4=10, D5-L1=28; Mean time post-injury: 167 mo.

Treatment: Participants had received a 300 IU injection of onabotulinumtoxin (OnaBXT) into the detrusor and were followed-up with 6 mo post-injection.

Outcome Measures: Cystomanometric bladder capacity (CC), first involuntary bladder contraction volume (ICV), maximum pressure of voluntary contraction (IC maxP), the filling pressure (fillP), maximum detrusor voiding pressure (maxP), maximum urinary flow (Qmax), post-void residual (PVR), and index of urethral resistance (BOOI)

1.     Significant increases in CC (p=0.002), IVC (p=0.003), and PVR (p=0.002) were seen post-treatment compared to baseline.

2.     No other significant differences were found.

Caremel et al. 2011

Canada

Case Series

N=11

Population: Mean age: 29 yr (range=21-40); Gender: males=11, females=0; Level of injury: C5 to T6, complete SCI (AIS A)

Mean time post-injury: 74 mo (range 18-163).

Intervention: Participants received intradetrusor botulinum neurotoxin A (BT) injections of 300 units of onaBTx (N=10) or 1000 units of aboBTx (N=3) (2 participants received 2 BT injections at 7 mo intervals using a different dosage), each injection=0.2ml, number of injection sites=10 (N=2), 20 (N=9) or 30 (N=2), on average BT injections were performed 57 d after the pre-ejaculation test (range 2 – 240 d) and 59 d prior to the post-ejaculation test (range 9 – 154 d).

Outcome Measures: Detrusor overactivity, urinary incontinence, void volume.

1.     BT treatment was effective in improving bladder function (overactivity and urinary incontinence) in 11 of 13 cases (85%)

2.     In 10 of 13 cases (77%) amplitude of detrusor contractions decreased.

3.     When compared with pre-BT treatment, there was a lower number of anterograde ejaculations post-BT (77% versus 54%) yet a higher number of retrograde ejaculations (23% versus 46%).

Pannek et al.

2009a

Switzerland

Case Series

N=27

 

Population: Mean age: 34.5; Gender: male=15, female=12; Severity of injury: complete=15, incomplete=12; mean time between injury and first OnaBTx treatment=62.9 mo.

Intervention: 300 IU of OnaBTx in 30ml saline solution injected into the detrusor muscle

Outcome Measures: the Qualiveen questionnaire, continence rate and treatment success rate

1.     Urodynamic variables including bladder capacity, reflex volume and detrusor compliance significantly improved. 21 of 23 participants became continent after first OnaBTx treatment.

2.     No significant differences in terms of urodynamic variables were reported between first and final treatment, however incontinence rate increased from 2 to 7 participants at final treatment.

3.     Long term success rate for incontinence was 74%. There is a significant decrease in improvement in maximum detrusor pressure before the 2nd and the final treatment, suggesting that detrusor contraction strength did not completely recover after the injection.

4.     Four participants reported mild temporary muscular weakness and 1 participant dropped out of treatment due to severe side effects.

Akbar et al. 2007

Germany

Case Series

N=44

Population: Mean age: 34.34 yr; Gender: males=10; females=15; Level of injury: paraplegic=15, tetraplegic=10.

Intervention: aboBTx injected intramuscularly into 20 detrusor sites for pediatric participants and 40 sites for adults. Participants were re-injected when there was a substantial return to baseline measures.

Outcome Measures: Detrusor compliance, bladder capacity and detrusor pressure. Follow-up was 3-5 yr from the study.

1.     After 1, 2, and 3 injections significant improvement (p<0.001) in:

·     Detrusor compliance

·     Maximum detrusor pressure

·     Bladder capacity.

2.     Prolonged efficacy of repeated injections in participants with neurogenic bladder function was seen over an average of 4.5 yr.

3.     No drug tolerance or changes in morphological appearance of the bladder was seen.

4.     Side effects were seen in 3 participants receiving a dose of 1000 U aboBTx, which was resolved by reducing the dose to 750 units.

Reitz et al. 2004

Switzerland

Case Series

Ninitial=231;Nfinal=200

Population: Neurogenic detrusor overactivity. Gender: males=131, females=69.

Intervention: Participants from 10 European medical centers who previously received 300 units of onaBTx into the detrusor were assessed.

Outcome Measures: Mean cystometric bladder capacity, reflex volume, bladder compliance, mean voiding pressure were assessed at 12 and 36 weeks post injection.

1.     Significant improvement in mean cystometric bladder capacity, reflex volume, bladder compliance and mean voiding pressure was seen at about 12 weeks post injection (p<0.0001).

2.     Complete continence was achieved in 132 of the 180 individuals with incontinence pretreatment.

3.     At 36 week follow-up, improvements in mean cystometric bladder capacity (p<0.0001), reflex volume (p<0.01) and mean voiding pressure (p<0.0001) remained.

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.