BoNT-A was initially introduced in urology for treating patients with neurogenic lower urinary tract dysfunction (NLUTD) due to chronic SCI ^[1][2][13,14]. Detrusor BoNT-A injection reduces the incidence of NDO and lowers intravesical pressure, which improves urinary incontinence ^[3][4][5][15,16,17]. Subsequent studies proved the efficacy of BoNT-A on autonomic dysreflexia (AD) in patients with high-level SCI, in addition to treating NDO and urinary incontinence in pediatric patients with myelomeningocele or other NLUTDs [6].

The U.S. Food and Drug Administration and several European countries approved a 200 U BoNT-A detrusor injection as the standard treatment dose for urinary incontinence caused by NDO in SCI patients ^[7][8][9][11,12,18]; however, preliminary studies used 300 U to demonstrate its therapeutic effect of increasing maximal bladder capacity and compliance and decreasing reflux volume ^{[10][11][12][13]}[19,20,21,22]. Compared with placebo, detrusor BoNT-A injection was effective in reducing NDO caused by SCI or multiple sclerosis ^[14][23]. Eventually, researchers compared the therapeutic efficacy of the 200 U and 300 U dosages and found that the former achieves comparable effects with possibly fewer adverse events (AEs), leading to the adoption of the 200 U dose by urologists ^[9][18]. Furthermore, repeat BoNT-A injections were found to have similar efficacy to the first one ^[15][24]. A pooled data analysis by Mangera et al. revealed detrusor BoNT-A injection in SCI patients could facilitate a decrease in the daily incontinence episodes (63%), the frequency of clean intermittent catheterization (CIC) (18%), and maximal detrusor pressure (42%) as well as an increase in the cystometric bladder capacity (68%) and reflux volume (61%) ^[6][16][6,25]. Detrusor BoNT-A injection can also significantly improve health-related quality of life (QoL) indexes ^[6][17][6,26] and decrease the rate of symptomatic urinary tract infection (UTI) in SCI patients ^[6][18][6,27]. The detrusor BoNT-A injection-induced improvement in bladder compliance and urinary continence can persist for up to nine months ^[4][19][16,28], and repeated injections can sustain improvement in continence and QoL ^[20][29].

However, symptom evaluation alone may not be sufficient. High intravesical pressure with potential upper urinary tract damage might be missed in some patients with urinary continence after detrusor BoNT-A injection ^[21][30]; therefore, a urodynamic examination might be necessary for some patients even with obvious symptomatic relief after detrusor BoNT-A injection ^[21][30]. Besides, detrusor BoNT-A injection usually impairs detrusor contractility, leading to a large postvoiding residual volume (PVR) or urinary retention in patients with NDO; hence, patients receiving detrusor BoNT-A injection may require CIC for large PVR and suffer from subsequent UTIs ^[3][15].

Several studies compared different BoNT-A injection methods for patients with NLUTD. Krhut et al. compared BoNT-A detrusor injection with submucosal injection in SCI patients with NDO and found no significant difference between the two groups regarding symptomatic improvement, change in urodynamic parameters, efficacy duration, and AEs ^[22][31]. Samal et al. also reported concurring findings as the two methods gave similar results in terms of urgency incontinence episodes, number of catheterizations, urodynamic profile, and efficacy duration ^[23][32]. Interestingly, Taha et al. compared a trigone-including injection with a trigone-sparing injection in SCI patients with refractory NDO and found that the former group had a significantly lower incontinence rate, higher complete dryness rate, and higher reflux volume ^[24][33]. No injection-related vesicoureteral reflux was found in either group. Another randomized control trial compared combined BoNT-A 160 U trigone-sparing and 40 U trigone-including injections with 200 U trigone-sparing BoNT-A injection for NDO in SCI patients ^[25][34]. Including the trigone resulted in superior outcomes for QoL, mean urinary incontinence episodes, complete dryness rate, mean voided volume, detrusor pressure, and involuntary detrusor contraction without any vesicoureteral reflux. In another randomized control trial, the effectiveness of combined BoNT-A injection (240 U into the detrusor and 60 U into the trigone) was compared to that of nontrigonal injection (300 U into the detrusor but not the trigone). The trial found that both methods had similar results, but the trigonal injection was found to be safer and more effective than the nontrigonal injection and did not increase the rate of vesicoureteral reflux ^[26][35]. The trigone has abundant sensory neural fibers and is highly sensitive to pressure changes, which possibly influences detrusor overactivity; therefore, the denervating effect of the trigone-including injection is more effective in inhibiting involuntary bladder contraction ^[27][36].

Treatment efficacy is a crucial factor for deciding whether SCI patients should receive a detrusor BoNT-A injection ^[28][37]. Certain pretreatment factors like higher maximum detrusor pressure and lower bladder compliance. Lower maximal cystometric capacity, and poor response after the first injection have been associated with higher treatment failure rates ^[29][30][31][38,39,40]. NDO patients with initially higher incontinence reduction rates after the first detrusor BoNT-A injection showed better outcomes for incontinence reduction and QoL during the subsequent treatment period ^[32][41]. Some NDO patients with poor response to the first dosage also reported gradually higher incontinence reduction after receiving subsequent BoNT-A therapy. Therefore, a second dose of detrusor BoNT-A injection must be given to patients who did not show a good response to the first injection before classifying them as poor responders.

The presentation of NLUTD depends on the level of SCI—patients with a suprasacral cord injury might develop NDO with or without DSD, and symptoms of frequency, urgency, with or without urgency urinary incontinence, and incomplete voiding ^[33][42]. Patients with a sacral lesion might present with a poorly contracting detrusor with incomplete voiding and/or stress-related urinary incontinence associated with a weak sphincter, while a cauda equina lesion may develop detrusor areflexia and incompetent sphincter relaxation ^[33][42]. SCI patients commonly have both voiding and storage symptoms ^[34][43]; targeting the detrusor for urinary incontinence might worsen bladder emptying ability, whereas targeting the urethral sphincter for voiding dysfunction might aggravate the incontinence. It is a challenge for both the urologist and the patient to balance between being dry and complete bladder emptying.

While a detrusor BoNT-A injection of 200 U or 300 U can improve bladder compliance and restore urinary continence in SCI patients with NDO ^[4][16], this treatment usually hampers detrusor contractility. A large PVR or urinary retention might become bothersome, and about 70% of patients require periodic CIC and develop subsequent UTIs ^[3][15]. Therefore, a lower dose (200 U over 300 U) of BoNT-A is sufficient to produce similar improvements in urinary incontinence and urgency episodes without altering the spontaneous voiding function that is required ^[35][36][44,45].

Dykstra et al. first reported the use of urethral sphincter BoNT-A injection to improve bladder emptying in SCI patients with DSD ^[37][46]. This injection can decrease the mean maximal urethral pressure, duration of DSD, and PVR for three to nine months ^[1][13]. Improved voiding and reduced CIC frequency also improve the QoL ^[38][2]. However, a urethral sphincter injection would increase the severity of urinary incontinence and urgency or urge urinary incontinence episodes, which might lead to patient dissatisfaction ^[38][39][2,47]. Exacerbated incontinence and urgency episodes might compel the patient to select detrusor BoNT-A injection subsequently ^[40][41][48,49].

The optimal condition for chronic SCI patients is self-voiding without urinary incontinence or severe urgency. In order to achieve this goal of treatment result, concomitant BoNT-A detrusor and urethral sphincter injections might be adopted in patients craving less urinary incontinence and preservation of spontaneous voiding. Huang et al. reported that combined BoNT-A (200 U) detrusor and (100 U) urethral sphincter injections might induce a significant reduction in both detrusor and urethral pressure without increasing PVR, daily CIC frequency, or daily pad use ^[42][50]. Another study with the same BoNT-A dosage revealed that a combined injection could lower the detrusor and urethral pressures to improve the patient’s QoL while protecting the upper urinary tract ^[43][51].

Sex-based differences are an important concern while treating patients with NDO or DSD. Male SCI patients can use an external urine collection device to prevent soiling and usually can do without being totally dry. On the other hand, female SCI patients tend to use a diaper and would rather prefer to be totally dry; if possible, be free of diapers and decrease the need for CIC to a minimum. A small dose of BoNT-A detrusor injection is adequate to increase bladder capacity and decrease urinary incontinence in this condition; Around 24% of patients can void by abdominal tapping (tapping the suprapubic area to induce reflex contraction of the bladder) without requiring CIC ^[44][45][52,53]. A dose–response study compared BoNT-A injections of 200 U, 100 U, and 50 U with placebo injections into the detrusor muscle ^[1][13]. The study found that the 50 U dose did not show any significant improvement over the placebo for any of the efficacy parameters. However, the 100 U dose showed some improvement over the placebo, although the observed magnitude of change was generally less favorable compared to that seen with the 200 U dose ^[1][13].

Before administering a BoNT-A detrusor injection in SCI patients, the following issues need to be considered:

• Behavioral modifications should be the primary strategy.
• BoNT-A injections could be considered in the case of failure of other treatments or intolerable adverse effects of oral medications, such as antimuscarinics or beta-3 agonists.
• Most patients require CIC after BoNT-A detrusor injection. Patients unable to perform CIC might not be suitable for this treatment.
• Regular monitoring is essential to check upper urinary tract function and prevent adverse effects and the occurrence of UTIs and large PVR.
• Repeated injections are required to maintain therapeutic efficacy in SCI patients.

Repeat detrusor injections are required to sustain the therapeutic efficacy of BoNT-A on NDO. An estimated 67% of SCI patients, who received BoNT-A injections for NDO, continued with repeat injections during a five-year follow-up ^[46][54]. Of these patients, 90% reported high satisfaction and were willing to consider periodic BoNT-A injections as a long-term treatment option ^[5][6][46][6,17,54]. Herbert et al. conducted a retrospective chart review for SCI patients with NDO who received BoNT-A therapy and reported a 59.1% adherence rate at 5 years and 50% at 10 years ^[31][40]. Baron et al. also described similar adherence rates (5 years: 63.9%; 10 years: 49.1%) ^[47][55]. The most common reasons for discontinuation were lack of efficacy and AEs, such as UTI, urinary retention, and hematuria ^[28][37].

Adherence to detrusor BoNT-A injections in SCI patients is highly associated with the treatment outcome ^[46][54]. Repeated injections allow the maintenance of favorable effects and hence, greater patient satisfaction ^[28][46][37,54]. However, SCI patients with voiding dysfunction are not equally satisfied with long-term urethral sphincter BoNT-A injections as they are with detrusor injections ^[48][3]. Only 35.6% of patients continued urethral sphincter BoNT-A injection therapy during a median follow-up of five years ^[48][3]. The low satisfaction rates after urethral sphincter injection were mainly caused by a high incontinence grade, inefficient therapeutic efficacy, and failure to help them wean off of CIC ^[48][3].

The most common AEs with BoNT-A detrusor injections are symptomatic UTI, urinary retention, and hematuria ^[49][4]. BoNT-A detrusor injections are effective in reducing detrusor pressure and urinary incontinence and increasing maximal bladder capacity ^[49][4]. However, they also impair detrusor contractility leading to subsequent large PVR or urinary retention. Although BoNT-A urethral sphincter injection can facilitate bladder emptying and increase the flow rate (duration around three to nine months), it also enhances the risk of urinary incontinence, urgency sensation, and de novo frequency ^[48][3]; seldom, patients may be disappointed by the AEs that exceed the therapeutic effect. Largely, dissatisfaction with BoNT-A urethral sphincter injection is rooted in amplified urinary incontinence, whereas larger PVR requiring CIC is the primary reason for discontent with detrusor injection ^[44][52].

Intolerable AEs often cause patients to forsake repeat BoNT-A injections, although these patients can achieve complete dryness after detrusor injections. Chen et al. retrospectively reviewed 223 patients with chronic SCI who received BoNT-A detrusor injections for NDO and urinary incontinence; only 108 patients (48.4%) continued with repeat injections during the mean ten-year follow-up ^[5][17]. Among those discontinuing BoNT-A therapy, 41 patients (46.6%) discontinued due to UTIs, while 15 patients (17%) deferred due to the burden of CIC. Likewise, Hebert et al. reviewed 128 SCI patients receiving repeated detrusor BoNT-A injections for NDO, of which 58 discontinued therapy over a median follow-up of ten years ^[31][40]. Seventeen patients stopped therapy due to AEs despite the therapeutic efficacy of detrusor BoNT-A injection.