Pre and post BTX-A urodynamics show BTX-A injection leads to reproducible changes in key urodynamic parameters including bladder capacity, maximum detrusor pressures (Pdet_max), compliance and NDO prevalence. In a 2017 systematic review of 12 studies and 293 pediatric patients with spina bifida, Hascoet et al. reported significant reduction in Pdet_max (32%–54%), increase in cystometric capacity (27%–162%), and improvement in compliance (28%–180%) on post-BTX urodynamic assessment in a majority of published series (23). In the single prospective randomized trial assessing the safety and efficacy of 50 U, 100 U and 200 U of BTX-A, dose-dependent improvements occurred in functional bladder capacity and maximal detrusor pressure (Pdet_max) from baseline at 6 weeks post-injection, with 200 U giving greater improvement relative to 50 U (10). Additionally, the percentage of patients demonstrating NDO decreased significantly compared to baseline (88%–94% to 45%–62%), with the greatest reductions reported in the 100 U and 200 U groups. In the extension study, these urodynamic improvements remained durable throughout 3 dose cycles (injection procedures) in patients receiving 200 U (13).

When assessing clinical outcomes, improvement in continence and avoidance of reconstructive procedures are the two most cited endpoints. BTX-A reliably reduces daytime urinary incontinence (UI) with Austin et al. reporting 1.3 fewer incontinence episodes per day at 6 weeks post-BTX across multiple dosing regimens (10). Continued improvements were seen in the extension study with repeated injections of BTX-A at 200 U resulting in further reduction of daytime UI from baseline (−1.8 episodes/day) (13). Other non-randomized studies report “complete resolution” of incontinence with rates ranging from 32%–100% in patients with some combination of NDO +/− poorly compliant bladders (23).

However, the literature remains unclear as to whether BTX-A reliably reduces the need for major bladder reconstruction. Figueroa et al. reported that only 18% (3/17) of subjects undergoing repeated BTX-A injections ultimately required augmentation cystoplasty (AC) over a four-year period, while Bowen et al. demonstrated that 61% ultimately proceeded to AC at a median of 36 weeks following initial BTX-A injections (16, 21). These studies attempt to elucidate whether BTX-A provides a durable “rehabilitative” effect or simply is a means of delaying higher-risk interventions. Larger, prospective studies have not assessed need for reconstruction, likely because AC is not an easily definable “outcome,” but rather is a complex, multi-faceted decision which is provider and family dependent. In our opinion, it remains unclear for which patients repeat Botox injections are a viable option for long-term management vs. part of a stepwise approach aiming to delay AC. Nonetheless, it is clear that many providers are using BTX-A prior to consideration of AC.

Several studies have focused on whether BTX-A is effective in poorly compliant, high-pressure bladders. One study by Tiryaki compared 9 patients with NDO to 7 patients with poorly compliant, “fibrotic” bladders and noted significant improvements in capacity and compliance (4.7–8.6 ml/cmH₂O) in the NDO group compared to no change in either capacity or compliance (3.1–3.5 ml/cmH₂O) in the poorly-compliant group (22). They concluded that BTX-A is “useless” in low-compliance bladders despite a small cohort of patients of which the majority (81%) only received a single injection of BTX-A.

Prior studies utilizing animal models have demonstrated that BTX-A can reverse detrusor hyperplasia and fibrosis in both the early and late-stage development of NLUTD (24, 25). More recently, clinical studies have also supported these findings. Softness et al. demonstrated that low-compliance bladders (<10 ml/cmH₂O) had significant improvement (+3 ml/cmH₂O) relative to high-compliance bladders (>10 ml/cmH₂O) with 35% of low compliance bladders being recategorized as high-compliance following BTX-A injection (18). Similarly, Naqvi et al. showed poorly compliant bladders demonstrated significant improvement in compliance as compared to an OAB/NDO cohort (+10.2 ml/cmH₂O vs. +3.9 ml/cmH₂O, p = 0.016) (17). Notably in the low compliance group in this study, 71% of subjects received multiple injections, suggesting that conclusions/determinations regarding efficacy of BTX-A made after a single injection may be premature.

Detrusor sphincter dyssynergia (DSD) is a urodynamic finding in individuals with a neurologic condition describing bladder outlet obstruction secondary to involuntary contraction of the urethral and/or periurethral striated muscles in the presence of a detrusor contraction (26). The gold standard for diagnosis is via needle electromyography, but the majority of centers do not have this ability and utilize patch electrodes and/or fluoroscopy on videourodynamics to make this diagnosis (27). The first urologic use of BTX-A was in 1988 for the treatment of DSD in adult males with spinal cord injury (SCI) by injecting BTX-A into the external urethral sphincter (28). Additional studies in adults with SCI have shown improvements in a variety of urodynamic and clinical parameters including reductions in maximum detrusor pressure (Pdet_max), maximum urethral closing pressure (MUCP), post-void residual (PVR), and incontinence episodes in individuals who received BTX-A injections for NDO + DSD or DSD alone (28–30).

Within the pediatric literature, however, the use of BTX-A for the treatment of DSD is quite limited (31–34). Typical injection doses for this indication have ranged from 50 U to 300 units. Currently, only one study exists that includes subjects who received intrasphincteric BTX-A for a neurologic etiology (31). In this single institution study over 10 years, 5 children underwent BTX-A injection for DSD and 2/5 (40%) had complete resolution of symptoms (improved uroflow, PVR <20, no UTI). Median response time was 4 months and only 1 individual received both intradetrusor and intrasphincteric injection (31) (Greer). Additional studies within the pediatric literature have focused on intrasphincteric BTX-A for individuals with dysfunctional voiding (non-neurogenic). These studies are also limited by their small sample sizes and retrospective nature, but do demonstrate encouraging improvements in PVRs and other subjective data (32–34). Overall, the current evidence does not support the routine use of intrasphincteric BTX-A for DSD in patients with NLUTD, but data from the adult SCI population and pediatric dysfunctional voiding populations are encouraging and warrants further study in a pediatric neurogenic population.

In 2020, the Spina Bifida Association (SBA) released its guidelines for the urologic management of individuals with spina bifida. The primary goals for management are threefold: (1) maintain normal renal function (“protect the upper urinary tract”), (2) achieve urinary continence as early as socially acceptable, and (3) maximize urologic independence (35). Important secondary outcomes include elimination of hostile bladder dynamics via medical management and reduction/elimination of operative reconstruction of the bladder. Notably, the use of BTX-A is not mentioned in these guidelines. However, because BTX-A is a low-risk, minimally invasive procedure that can improve demonstrated urodynamic and clinical parameters in pediatric patients with NLUTD, BTX-A injections is an excellent option for achieving many of these key primary and secondary urologic goals identified by the SBA working group.

Early management of pediatric NLUTD includes the initiation of CIC and anticholinergic or B3 agonist medications for the treatment of urinary incontinence in the setting of upper tract changes, recurrent symptomatic UTI, or bladder hostility noted on UDS (35). Historically when these initial management strategies fail, “refractory NLUTD” was managed with open surgical procedures such as AC to increase bladder capacity and create a lower-pressure reservoir, ultimately protecting the upper urinary tract. However, the morbidity of these procedures is well known with prolonged hospital stays and a ten-year reoperation rate of 44% (36). Because of this, BTX-A use is increasing among pediatric urologists, which may prevent or delay need for AC (37). Prior population level studies support this, demonstrating stable or declining rates of AC in the setting of increased BTX-A use pediatric patients in the United States (38–41).

Given the variety of urodynamic and clinical benefits of BTX-A, it can be introduced and utilized in a variety of ways. BTX-A can be introduced “early” in cases of NDO and/or worsening compliance/detrusor pressures with associated urinary incontinence to decrease spasticity and improve capacity, reducing UI episodes in combination with appropriate CIC intervals (10, 17, 20, 21). Alternatively, BTX-A can be introduced “late” in individuals with poor compliance (<10 ml/cmH₂O), high Pdet_max (>40 cmH₂O), or upper tract changes on videourodynamics or renal ultrasound to reduce bladder hostility. Unfortunately in the latter group, preprocedural predictors for BTX-A success have not been identified or defined although some studies have shown some success (16–18).

Therefore, it would be our groups preference to introduce BTX-A earlier in the management of NLUTD when able to prevent and reverse early bladder remodeling. However, this is not always feasible given rapid clinical deterioration for some patients or family preferences regarding the need for general anesthesia. BTX-A is an option for patients with higher risk bladder function, and injection may improve compliance by shifting pressure curves into a safer zone where timely CIC can reduce the exposure of the upper tracts to high pressures (16).

In most studies to date, the effects of only a single injection of BTX-A have been reported to make determinations regarding the efficacy of BTX-A in pediatric patients. Despite its relatively long duration of action, the efficacy of BTX-A wanes after 3–6 months requiring repeated injection for sustained effects (7). In adult patients with NDO, repeated injections are commonplace and the need for repeat procedures are often dictated by the recurrence of symptoms such as urinary incontinence.

In the pediatric literature, several studies have reported on the effects of repeat injections. In the single randomized prospective study by Franco et al., repeat injections with 200 U led to consistent improvements in daytime UI and high patient satisfaction (75%) based on a modified treatment benefit scale (13). Additionally, improvements in UDS parameters such as capacity, Pdet_max, and proportion of patients experiencing NDO were noted throughout all 3 treatment cycles during the study period. In the study by Bowen et al., 39 subjects underwent 165 injections with the median number of injections per subject of 4 (IQR 3–7) (16). Of the 26 subjects deemed “at-risk” for AC, 16 (61.5%) went on to AC at a median of 36 months after a median of 4.5 injections prior to AC. Another study by Naqvi reported that 23% of patients ultimately required AC. In this study, significant improvements were seen in “low compliance” bladders with a median compliance change from 6.3 ml/cmH₂O at baseline to 14.1 ml/cmH₂O after BTX-A and consistent UDS improvements were maintained with repeat injections (17). Therefore, repeated injections should be considered for most patients unless there is no response/worsening on UDS and/or clinical parameters at first post-BTX evaluation.

More recent literature has focused on surgical decision-making surrounding the choice between BTX-A and AC. Li et al. performed a retrospective review of 14 patients who had AC and 50 patients who had BTX-A over a 5-year period and identified 10 key clinical factors that influenced management decisions (42). Surprisingly, they found that “desire for independence/continence” and “reduced bladder capacity” were significantly associated with AC whereas factors typically associated with bladder hostility were associated with BTX-A. This study highlights the importance of shared decision-making with patients and families regarding management decisions for pediatric NLUTD.