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Botulinum Toxin for Bladder Emptying

Botulinum toxin is an exotoxin produced by the bacteria Clostridium botulinum. As noted previously (see 3.1.2 Toxin therapy for SCI-related Detrusor Overactivity), it has been used for many conditions associated with muscular overactivity and specifically for NDO. Among individuals with sphincter overactivity post SCI, botulinum toxin may be administered into the external urethral sphincter causing the muscle to relax resulting in improved drainage (DeSeze et al. 2002). The toxin works by inhibiting acetylcholine release at the neuromuscular junction and relaxing the muscle, an effect that gradually wears off over the months following injection. Injections of botulinum toxin A into the sphincter may improve emptying and possibly eliminate the need for catheterization.

Table 9 Bladder Emptying through Botulinum Toxin

Author Year

Country
Research Design
Score
Total Sample Size

MethodsOutcome
DeSeze et al. 2002

France

RCT

PEDro=7

N=13

 

Population: Mean age: 45.5 yr; Gender: males=12, females=1; Level of injury: paraplegic=9, tetraplegic=4.

Intervention: Participants were randomly placed into two groups: 1) botulinum A toxin group (BTX) received one injection of 100 IU onaBTX in 4 mL of 9% saline into the external urethral sphincter or 2) lidocaine group (LG) received an injection of 4mL of 0.5% lidocaine into the external urethral sphincter.

Outcome Measures: Maximal urethral pressure, maximum detrusor pressure and detrusor sphincter dyssynergia. One month after the injections, the efficacy and tolerance was assessed.

1.     The BTX group showed significant decrease in post-voiding residual volume (PRUV; p<0.01) and maximal urethral pressure (p<0.04). However, no significant change was seen in the lidocaine group.

2.     After one month, autonomic dysreflexia disappeared in participants from BG but remained unchanged in the lidocaine group.

3.     Participants in the BTX group gave a significantly higher mean efficacy score compared to the LG group.

4.     No significant difference was seen in tolerance between the two groups.

Dykstra & Sidi 1990

USA

RCT

PEDro=5

N=5

 

Population: Mean age: 32 yr; Gender: males=5, females=0; Level of injury: cervical; Severity of injury: complete=4, incomplete=1; Mean time post-injury=14 yr.

Intervention: Injection of 140 U of botulinum A toxin (or saline) into 3-4 sites of the external urethral sphincter via cytoscope followed by two more injections of 240 U.

Outcome Measures: Cystometry to obtain post-void residual (PVR), urethral pressure profiles, bladder pressure on voiding obtained pre-post 3 week treatment periods.

1.     OnaBTx reduced bladder flow obstruction as indicated by decreases in all measures.

2.     A mean decrease from baseline to 3 weeks post injection was seen in:

·       Urethral pressure profiles: 22cm H2O

·       Post void residual volume: 118cc

·       Bladder pressure: 25cm H2O

3.     No changes were seen with saline injections (n=2) for these parameters.

4.     3 of 5 participants noted mild, generalized upper extremity weakness that caused difficulty with transfers and some ADLs, gradually subsiding over 2-3 weeks. No other adverse events reported.

Dykstra et al. 1988

USA

RCT

PEDro=3

N=11

Population: Mean age: 29 yr; Gender: males=11, females=0; Level of injury: C=10, T=1; Severity of injury: complete=11, incomplete=0.

Intervention: Three protocols were created: 1) subjects were injected (into the urethra) 20 U of toxin initially and 40 U in the second week. All subsequent wk the participants were given 80 U doses. 2) The initial dose was 80 U and the second week dose was 160 U, followed by weekly doses of 240 U. 3) Participants were injected with 140 U of toxin the first week and all subsequent weekly doses were of 240 U.

Outcome Measures: Urethral pressure, post-void residual urine volume, autonomic dysreflexia.

1.     The urethral pressure decreased an average of 27cm after treatment.

2.     Post-void residual urine volume decreased by an average of 146cc after the toxin injections.

3.     However an increase in post-void residual volume and urethral pressure was observed as the effects of the toxin diminished.

4.     No UTIs occured as a result of the cytoscopic injections.

5.     More than half the participants who suffered from autonomic dysreflexia noticed improvement in the dysreflexia after toxin injections.

Petit et al. 1998

France

Prospective Controlled Trial

N=17

Population: Mean age: 35 yr; Gender: males=17, females=0; Level of injury: paraplegic=3, tetraplegic=8.

Intervention: All participants received endoscopic injection of 150 IU BTx diluted to 4mL with 0.9% saline solution into the external urethral sphincter at 3 or 4 points.

Outcome Measures: Post voiding residual urine volume (PRUV), bladder pressure on voiding, urethral pressure, tolerance. Assessment was made after 15 d, 1 mo, 2 mo, 3 mo, 6 mo, and 1 yr.

1.     One mo after BTx injection a significant decrease was seen in PRUV (p<0.001), urethral (p<0.001) and bladder pressure on voiding (p<0.01).

2.     Modality of voiding was improved in 10 participants.

3.     The effect of BTx lasted from 2 to 3 mo in 3 participants and 3 to 5 mo in 2 participants.

Schurch et al. 1996

USA

Prospective Controlled Trial

N=24

Population: Mean age: 32.2 yr; Gender: males=24, females=0; Level of injury: paraplegic=11, tetraplegic=13; Mean time post-injury=40.6 mo.

Intervention: Participants were divided into one of three treatment protocols: 1) 4 transurethral injections of 25 IU botulinum A toxin repeated 1 to 3 monthly; 2) 4 injections of 25 IU botulinum A toxin given monthly for 3 months and repeated after 6 or 12 months; 3) 1 transperineal injection of 250 IU botulinum A toxin per month for 3 months and then repeated after 6 or 12 months.

Outcome Measures: Post void-residual (PVR), cultures of urine samples and complete urodynamic examination was performed.

1.     Decreased PVR from 450 to 50 ml were seen in 9 out of 24 participants.

2.     All groups showed significant improvement in: Maximum urethral pressure (p<0.0001), duration of detrusor sphincter dyssynergia (p=0.02), and basic urethral sphincter pressure (p=0.01).

3.     Injection of botulinum A toxin improved vesicourethral function for only 2 to 3 mo, while repeated injections lasted 9 to 13 mo.

4.     Transperineal injections were not as effective as transurethral injections on maximum urethral pressure.

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 sites, 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).

Yang et al. 2015

China

Pre-Post

N=15

Population: DESD; Mean age: 40.5 yr; Gender: males=15; ASIA classification: A=7, B=4, C=3, D=1; Mean time post-injury: 10.13 mo.

Treatment: All participants received a 100 U onabotulinumtoxinA (OnaBTX) injection into the external urethral sphincter.

Outcome Measures: Maximum detrusor pressure (Pdet), detrusor leak point pressure (Plp), maximum pressure on urethral pressure profilometry, post-void residual volume (PVR), and maximum flow rate (Qmax).

1.     Plp (p<0.01), urethral pressure profilometry (p<0.01), PVR (p<0.01) all significantly decreased with treatment from baseline to post-injection. Qmax significantly increased (p=0.01), while Pdet was not significantly impacted by treatment.
Kuo 2013

Taiwan

Pre-Post

N=55

Population: Injury etiology: SCI=47, MS=6, myelitis=2; All participants 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.

Chen et al. 2010

Taiwan

Pre-Post

N=18

Population: Mean age: 36.7 yr; males=18, females=0; Level of injury: C=13, T=5; Severity of Injury: AIS A=9, B=5, C=3, D=1.

Intervention: Participants were injected with 100U of onaBTx through the perineum into the external urethral sphincter.

Outcome Measures: Detrusor pressure, detrusor leak point pressure, pure pressure, intramuscular electromyography (iEMG), static pure pressure were taken at baseline and 4 weeks post injection. Post-void Residual (PVR) was measured at baseline, 1 mo, 2, mo, 4 mo and 6 mo post injection.

1.     No signficant change was seen in detrusor pressure and detrusor leak point pressure post injection.

2.     1 mo post injection, significant reduction was seen in:

·       Pure pressure, p=0.023

·       iEMG, p=0.008

·       Static pure pressure, p=0.012

3.     Significant reducing in PVR was seen up to 6 mo post injection, p<0.05.

Tsai et al. 2009

Taiwan

Pre-Post

N=18

Population: Mean age: 33.8 yr; Level of injury: C=8, T=10; Severity of injury: AIS A=14, B=1, C=3

Intervention: Individuals with SCI and detrusor sphincter dyssynergia, voiding difficulty, and inadequate response to oral medications were injected with 100 units of BTX-A transperineally into the external urethral sphincter with electromyography and fluoroscopic guidance.

Outcome Measures: Post-Void Residual (PVR), leak point pressure, maximal intravescical pressure, urethral pressure.

1.     Post BTX-A injections, significant improvement and clinically successful results were seen in postvoid residual volume (100%), leak point pressure (down to<40 cm H20 in 72%), maximal intravesical pressure (down to<40 cm H20 in 72%) and urethral pressure (94%) (p<0.05).

2.     BTX-A injection also resulted in improvement in the quality of life index, p<0.01.

Kuo 2008

Taiwan

Pre-post

N=33

Population: Mean age: 41 yr; Gender: males=22, females=11; Level of Injury: C=9, T=12, L=5, MS=5, Transverse myelitis=2.

Intervention: Prospective investigation of satisfaction and Quality of Life (QoL) after urethral injection of 100 U BTX-A in individuals with chronic suprasacral SCI & Detrusor sphincter dysneriga.

Outcome Measures: Urodynamic study, Post void residual incontinence grade (PVR) (0 – 3), difficulty urinating (0 – 3), QoL. Successful outcome=moderate or very satisfied whereas not or mildly satisfied=failure of treatment, Incontinence Impact Questionnaire (IIQ-7).

1.     Significant decrease in voiding detrusor pressure was seen 45.7± 22.7 vs. 30.7±15.5 cm H20 (p=0.016)

2.     Significant increase in max flow rate (p=0.047) and decrease in PVR (p=0.025) was seen.

3.     A decrease was seen in difficulty urinating (78.8%), PVR (69.7%), UTI frequency (67%), autonomic dysreflexia (50%).

4.     Significant improvement in QoL index of IIQ-7 was seen at 3 mo compared to baseline (p=0.001) but no such improvement was seen in UDI-6 (urogenital Distress inventory).

Phelan et al. 2001

USA

Pre-Post

N=21

Population: Age range 34-74 yr; Gender: males=8, females=13.

Intervention: Botulinum A toxin (80-100 units) injected via cytoscopic collagen needle/cytoscope into the external sphincter at 3, 6, 9 and 12 o’clock. Outcome Measures: Able to void without catheterization.

No statistics provided.

1.   19/21 subjects voiding without catheterization after injection.

2.   14 reported significant subjective improvement in voiding patterns.

3.   Postoperative PVR by 71%.

Soler et al. 2016

France

Case Series

N=99

Population: DSD; Mean age: 38.4 yr; Gender: males=99; Level of injury: tetraplegia=72, paraplegia=27; Mean time post-injury: 99.1 mo.

Treatment: Participants were injected with 100 U of onabotulinumtoxinA (OnaBTX) into the urethra. Data was collected at baseline and at 1 mo post-injection.

Outcome Measures: Treatment success, post-void residual (PVR) volume and %, occurrence of dysuria, retention, voiding mode and autonomic dysreflexia (AD) signs.

1.     For the 48 participants whose injections were effective, the effectiveness lasted for a mean time of 6.5 mo.

2.     PVR volume (p<0.01), PVR% (p<0.01), and dysuria (p<0.01) significantly decreased with treatment from baseline to 1 mo post-injection.

3.     Retention was present in 19 participants initially, post-treatment, 4 had excellent retention, 9 improved, and 6 remained unchanged. Overall treatment improved retention (p<0.01).

4.     At baseline, voiding mode was distributed across participants as 51 spontaneous, 29 spontaneous + CIC, 12 CIC only, and 4 indwelling catheter. Post-treatment, 68 participants used spontaneous voiding, 22 spontaneous voiding + CIC, 9 CIC only, and 0 participants used an indwelling catheter.

5.     All participants initially had signs of AD. With treatment 49 cases disappeared, 20 improved and 13 were unchanged (p<0.01).

Discussion

Detrusor external sphincter dyssynergia and associated high bladder pressures, vesicoureteral reflux, and frequent UTIs are associated with poor long-term outcomes in persons with SCI. These individuals may develop upper tract deterioration and/or suffer incontinence and poor QoL. Injection of botulinum toxin into the external urethra reduces bladder pressures, improves the incidence of UTI, and in some individuals, normalizes bladder emptying (Tsai et al. 2009; Kuo 2008). The impact of increased incontinence after sphincter injection, along with improved urodynamic parameters were studied by Kuo (2008; 2013). While this author cautions that QoL can decrease due to increased incontinence experienced by some individuals, careful individual selection and combinatorial approaches may allow some to benefit from the clearly evident improvement in urodynamic parameters and UTI incidence. Tsai et al. (2009) showed statistically significant improvement in QoL post-injection but did not reveal data on incontinence. Huang et al. (2016) also showed significantly improved QoL as well as data demonstrating complete dryness in all participants at 2 weeks sustained at 8 and 16 weeks.

Kuo (2013) found that combined detrusor and additional low-dose urethral sphincter BTX-A injections in individuals with incomplete SCI and detrusor sphincter dyssynergia, was effective in producing less urinary incontinence and preservation of spontaneous voiding. As well, participants with detrusor sphincter dyssynergia treated only with detrusor BTX-A injections (i.e., 200 U) improved QoL ratings to a greater extent than participants treated with only urethral injections (i.e. 100 U).  Yang et al. (2016) performed transrectal ultrasound-guided catheter transurethral injections (100U) into the external urethral spincter to treat DESD and achieved a success rate of 75.2%. In a case series of 99 individuals who received urethral injections of botulinum toxin to treat DSD, good outcomes were observed in 89% of participants; were the presence of detrusor contractions and normal bladder neck activity were strong predictors of good outcomes (Soler et al. 2016).

The improvements found in post-voiding residual volumes demonstrated by Kuo (2008, 2013) and Tsai et al. (2009) were initially desmontrated by DeSeze et al. (2002); who conducted a double blind RCT in which lidocaine as a control injection (n=8) was compared to botulinum toxin A (BTxA) as active treatment (n=5). DeSeze et al. (2002) found BTxA improved post void residual volume in individuals with SCI to a greater extent than lidocaine. One month following the injection of BTxA into the external sphincter, post-void residual volume decreased significantly from 159.4 mL to 105.0 mL and participants who previously presented with autonomic dysreflexia no longer exhibited symptoms.

In the clinical setting, a test dose of BTX-A combined with integrated electromyography is the optimal method for evaluation of dose and efficacy. Chen et al. (2010) demonstrated that a single low dose (100 U) of BTX-A, applied into the external urethral sphincter cystoscopically, could be monitored 4 weeks post-injection for objective measures of efficacy. Severe urethral sphincter spasticity as documented through integrated electromyography served as an indication for repeat injections or higher doses. Additional studies demonstrated a decrease in symptoms of autonomic hyperreflexia in at least 60% of participants (Tsai et al. 2009, Kuo 2008, Dykstra et al. 1988; Dykstra & Sidi 1990; Petit et al. 1998; Schurch et al.1996). Almost all participants showed post-injection sphincter denervation on electromyography resulting in temporary relief of these symptoms for approximately 2-3 months; afterwhich additional subsequent BTxA injections were needed to maintain results (Dykstra et al. 1988; Dykstra & Sidi 1990).

Schurch et al. (1996) compared the effectiveness of transurethral versus transperineal botulinum toxin A injections in a prospective controlled study. The study found that transurethral botulinum toxin injections were more effective in reducing urethral pressure than transperineal injections. However, other symptoms were improved with either injection method. Tsai et al. (2009) described a method of transperineal sphincter injections using fluoroscopic guidance and electromyography that dramatically improved bladder emptying, with most individuals returning to voiding. Participants were able to avoid frequent ICs with three being able to discontinue indwelling catheterization altogether.

Schurch et al. (1996) also revealed the additive effects of recurrent BTx injections resulting from the prolonged inhibition of acetylcholine release. After 3 monthly injections, the therapeutic effects of BTx lasted as long as 9 months compared to only 2-3 months with 1 injection. Women, as a result of anatomial differences, often have greater difficulty performing self-catheterization than do men. Therefore the “normalization” of voiding as a result of botulinum toxin injections into the sphincter may play an even greater role in the urologic management of females with SCI. Phelan et al. (2001) were the first to demonstrate the successful use of botulinum toxin A in women. Their study of 13 females showed that all but one was able to spontaneously void following botulinum A injection. More study of the long term outcomes of “spontaneous voiding” after sphincter injection in women is required.

Chen et al. (2010) evaluated the effects of a single transrectal ultrasound-guided transperineal injection of 100 U onaBTx to the external urethral sphincter to treat DESD. As the prostate gland represented a key landmark in the transrectal ultrasound-guided injection, the study was limited to male subjects. Video-urodynamic results obtained at an average of 33.3 days postinjection showed significant reduction in dynamic urethral pressure, integrated electromyography, and static urethral pressure. The onaBTx injection did not produce a significant decrease in maximal detrusor pressure. This was the first study to demonstrate the effect of transrectal ultrasound -guided transperineal onaBTx injection into the external urethral sphincter and the potential for achieving outcomes similar to transurethral injection.

While not specifically mentioned in the above studies, a group of individuals likely to benefit from injections of BTX-A into the sphincter are men who have persistently elevated bladder volumes while using condom drainage. Reasons why individuals with SCI chose condom drainage include a reluctance to perform self catheterization or alternatively there is persistent incontinence on IC regimes despite adequate trials of anticholinergic medication. These individuals could theoretically benefit from improved drainage, as residual urine is a common cause of UTI, and accompanying elevated bladder pressures place the upper genitourinary tracts at risk. Whether or not such individuals actually resume “voiding” to allow for the discontinuation of condom drainage altogether has not been addressed.

Botulinum toxin therapy is advantageous as it allows one to avoid major surgical procedures and their associated risks. Botulinum toxin injections decrease the resistance to urine outflow by relaxing the external sphincter. This in turn decreases post-void residuals in 70% of individuals, with acceptable voiding pressures (Tsai et al. 2009). Symptoms such as autonomic dysreflexia and UTI incidence also appear to be reduced. Sphincter denervation, however, is transient and repeated injections are required to maintain therapeutic results. Post-injection urodynamic studies should be conducted to document that resultant voiding pressures fall in the acceptable range. For individuals with SCI with neurogenic bladder that do not experience unacceptable incontinence, botulinum toxin injections into the external sphincter can improve bladder emptying. Further study is required to determine whether or not recurrent sphincter injections and related improvements in voiding pressures and UTI incidence result in better long term upper tract outcomes. Furthermore, to ensure widespread clinical uptake studies are needed to identify the individuals who are best suited to maximize the benefits of sphincter injections while avoiding unacceptable incontinence.

Conclusion

There is level 1 evidence (from one RCT and several controlled and uncontrolled trials; DeSeze et al. 2002) that botulinum toxin injected into the external urinary sphincter may be effective in improving outcomes associated with bladder emptying in persons with neurogenic bladder due to SCI.

There is level 4 evidence (from one case series; Soler et al 2016) that the presence of detrusor contractions and normal bladder neck activity may be strong predictors of good outcomes for urethral injections of botulinum toxin to treat DSD.

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

The presence of detrusor contractions and normal bladder neck activity may be strong predictors of good outcomes for DSD treated with BTX.