Intravesical Botox: An Effective Therapy for Refractory Monosymptomatic Nocturnal Enuresis

ABSTRACT

Aim

Monosymptomatic nocturnal enuresis (MNE) significantly impacts many children, with substantial patient groups refractory to conventional first‐line treatments. Intravesical Botox is used for various refractory functional voiding disorders in children, but its efficacy in MNE has not been widely established. This study aimed to determine the efficacy of intravesical Botox in children with refractory monosymptomatic nocturnal enuresis.

Methods

A retrospective analysis was conducted of 22 children with MNE (median age 11 years; 19 males) treated with intravesical Botox injection over a 6 year period. All participants had previously failed desmopressin, and the majority had trialled an enuresis alarm and oxybutynin. Each child received 200iU of Botox injected into the detrusor muscle. Treatment outcomes were classified as complete (100% reduction in wet nights), partial (50%–99% reduction), or no response (0%–49% reduction).

Results

Prior to treatment, median number of wet nights was six per week. Following the final injection, complete response was observed in 8 of 22 (36%) children, partial response in 7 of 22 (32%), and no response in 7 of 22 (32%). Median reduction in wet nights was 2.5 per week. Median duration of response for those experiencing relapse was 11 months. No intra‐operative complications occurred. Post‐operative complications were mild and self‐resolving, limited to transient haematuria/pain and dysuria in isolated cases, with no instances of urinary tract infection or retention.

Conclusions

Intravesical Botox injection is an effective, well‐tolerated treatment option for children with refractory monosymptomatic nocturnal enuresis, demonstrating a sustained response in a significant proportion of patients. This intervention presents a valuable option for treating this multi‐faceted condition.

1. Introduction

Onabotulinum toxin A (Botox, Allergan, Irvine, CA, USA) is commonly used as an intravesical injection in children with functional voiding disorders, though its use has not previously been established in the context of nocturnal enuresis. The current mainstay of treatment for nocturnal enuresis includes enuresis alarms and desmopressin. Enuresis alarms are unsuccessful in 30%–50% of children, and approximately half to two‐thirds of children experience recurrence of symptoms after cessation of desmopressin [1, 2, 3, 4, 5, 6]. Anticholinergics, mirabegron and imipramine or alternate antidepressants have been described as second and third‐line treatment options.

Nocturnal enuresis is a common condition among the paediatric population, affecting up to 10% of 7 year olds, and approximately 3% of teenagers [7]. It often profoundly impacts psychosocial wellbeing, affecting quality of sleep, self‐esteem and may result in avoidance of social activities such as camps and sleepovers. Almost two‐thirds of children report that enuresis has a significant impact on their quality of life [7, 8, 9, 10]. Successful treatment can restore self‐confidence and improve sleep quality, and in turn positively influence daytime executive function [10, 11].

Nocturnal enuresis is likely underpinned by: abnormal bladder storage ability and/or detrusor stability, the level of arousal during the phases of sleep (somnolence), and nocturnal urine production may also play a role [12, 13]. It is possible that by achieving neuromuscular stabilisation of the detrusor and improving functional capacity and stability, intravesical Botox injections could contribute to the management of refractory nocturnal enuresis. One previous study including 50 patients supports this hypothesis, in which a partial or complete response was observed in 94% of cases [14]. The present study aims to further determine the safety and efficacy of intravesical Botox in the management of monosymptomatic nocturnal enuresis (MNE).

2. Material and Methods

The medical records of all children with MNE treated with intravesical Botox injection by one surgeon over 6 years (January 2018–December 2023) were retrospectively analysed. All children included in the study experienced MNE as defined by the ICCS, that is, enuresis without any of the following daytime lower urinary tract symptoms: daytime incontinence, urgency, voiding difficulties, abnormally low or high daytime voiding frequency [15]. Patient demographics and previous treatments were noted.

All children received 200iU of botulinum toxin A (Botox, Allergan, Irvine, CA, USA). The product was diluted into 20 mL of normal saline with a sterile technique and injected in twenty 1 mL aliquots. Rigid cystoscopy was performed with a Storz Paediatric Cystoscope (9.5Fr) under a general anaesthetic. A Williams Cystoscopy Injection Needle (Cook Medical) was utilised for intra‐detrusor injection, which has a 23G needle and 8 mm long tip. The technique utilised intramuscular (detrusor) injections (up to a 6 mm depth) commencing in the midline trigonal region (avoiding the ureteric orifices and the ureteric intravesical course) and expanding over the posterior, superior and lateral aspects of the bladder (base and dome). All children received 25 mg/kg of intravenous cephazolin at induction. All children were routinely reviewed at 4 weeks post‐operatively, at which time treatment response was recorded, with subsequent follow‐up based on clinical course (for at least 12 months post‐operatively).

The severity of enuresis was classified as frequent (greater than or equal to four wet nights per week) or infrequent (less than four wet nights per week) as per the International Children's Continence Society (ICCS) recommendations [15].

Treatment outcomes were characterised as “no response” (0%–49% reduction in wet nights per week), “partial response” (50%–99% reduction) or “complete response” (100% reduction) as per the ICCS recommendations [15]. Treatment outcome was assessed following the final treatment cycle when multiple treatments were undertaken on the same child in order to minimise recall bias.

3. Results

During the study period, 26 children were treated with intravesical Botox injection for MNE. Of these, 22 children (3 females and 19 males) were included in the final analysis. Four children were excluded from the study due to inadequate follow‐up. Median age at first treatment was 11 years (range 7–15 years).

Past treatments included desmopressin in all children, enuresis alarm in 12 children (55%) and, in combination with desmopressin, oxybutynin in 14 children (64%), mirabegron in two children, and solifenacin in one child. Two children had received one treatment cycle prior to the study period. Proactive management of bowel dysfunction, where present, was a mandatory prerequisite prior to the initiation of any bladder‐directed pharmacotherapy. Posterior urethral valves were diagnosed and resected at the time of cystoscopy in five boys (5/19, 26%). Co‐existing neuropsychiatric disorders were diagnosed prior to treatment in two children. This included Attention‐deficit/hyperactivity disorder (ADHD) in one child, and Autism Spectrum Disorder (ASD) and ADHD in one child.

Before treatment, 17 children (77%) experienced frequent nocturnal enuresis (greater than or equal to four wet nights per week) and five children (23%) experienced infrequent nocturnal enuresis (less than four wet nights per week). The median number of wet nights per week prior to the first injection procedure was six nights (IQR 4–7 nights). The number of injection procedures required per patient during the study period is outlined in Table 1. Repeat treatments were performed only in those who had a partial or complete response to previous treatment cycles. Two children underwent a further injection procedure following the study period.

TABLE 1.

Number of injection procedures per child during the study period.

Number of injection procedures	n (%)
1	14 (64%)
2	4 (18%)
3	3 (14%)
4	0 (0%)
5	1 (5%)

Complete response was observed in 8/22 (36%) of children, partial response in 7/22 (32%) of children, and no response in 7/22 (32%) of children. Median number of wet nights per week following the final injection procedure was 1.5 (IQR 1–2 nights), with a median reduction in number of wet nights of 2.5 nights per week (IQR 0–4.75 nights).

Of those who experienced a complete response to treatment, 2/8 (25%) of children had experienced no further episodes of nocturnal enuresis after a 6 year duration of follow‐up. Of these, one child was treated with a single injection procedure, and the other had two treatment cycles with a 12 month interval between procedures. The median duration of response in those who experienced a relapse of symptoms was 11 months (IQR 5–12 months). The median time between treatment cycles in children who underwent multiple treatment cycles was 12 months (IQR 10–16 months).

Desmopressin was continued post‐operatively in eight participants (all male). Within this subgroup, two achieved a complete response, four demonstrated a partial response and two showed no response. One participant with no response subsequently transitioned to multimodal therapy with the addition of mirabegron.

Among the five boys (26%) with incidentally diagnosed PUV, outcomes varied according to the treatment sequence. Two patients underwent a single combined procedure of PUV resection and Botox injection, resulting in one complete and one partial response. A further two children achieved a complete response after a second treatment cycle; notably, these patients received Botox alone during the second stage without requiring repeat valve resection. Finally, one child who underwent PUV resection and Botox during two separate procedures remained a non‐responder.

There were no intra‐operative complications recorded. Post‐operative complications included haematuria and pain in one boy which self‐resolved within 24 h of the procedure, and one boy with dysuria during the first month following the procedure which subsequently self‐resolved (valve resection was also performed). One child who had an initial complete response to treatment subsequently had an increase in frequency of nocturnal enuresis at 3 months following the procedure. There were no instances of post‐operative urinary tract infection and no cases of urinary retention.

4. Discussion

Nocturnal enuresis is a common problem with significant impact on quality of life, and in many cases is refractory to current management options. Intravesical Botox injection can provide an alternative treatment option. The present study investigated its efficacy in this context, and found over two‐thirds (68%) achieved some impact on their symptoms with this treatment. This demonstrates clinical impact and safety particularly when included in a multi‐modal treatment pathway.

Nocturnal enuresis pathogenesis is multifactorial, with nocturnal polyuria, detrusor instability and high arousal thresholds all having a fundamental role [12]. Studies have previously demonstrated uninhibited detrusor contractions in enuretic children while asleep, occurring more commonly among children whose symptoms do not respond to desmopressin [16, 17]. This is clinically reinforced by symptom resolution with anticholinergic treatment.

The therapeutic efficacy of intravesical onabotulinum toxin A (Botox) in MNE likely stems from one of two mechanisms. While these children lack daytime incontinence, they often present with a ‘subclinical’ bladder phenotype—either characterised by low functional bladder capacity or detrusor instability that is successfully compensated for during waking hours through frequent or urgent voiding. By increasing functional capacity and mitigating this underlying instability, Botox provides therapeutic benefit.

The overall mechanism of action of intradetrusor Botox is probably multifactorial (via both efferent and afferent pathways) and incompletely understood. In the efferent system, it inhibits the presynaptic release of acetylcholine at the neuromuscular junction, leading to localised paralysis of the targeted muscle fibres and a reduction in involuntary muscle contractility [18]. Simultaneously, it modulates afferent signalling by desensitising unmyelinated C‐fibres in the urothelium and downregulating the release of sensory neurotransmitters like adenosine triphosphate [19, 20]. By shifting the balance towards increased nitric oxide release, Botox effectively expands functional bladder capacity, providing a physiological buffer.

It is important to consider the efficacy of intravesical Botox in comparison to already established treatments in MNE. In the present study, one‐third of children achieved a complete response, and an additional third achieved a partial response. All children had no response to desmopressin, and the majority (55%) had also trialled an enuresis alarm prior to intravesical Botox. Based on Cochrane reviews, the enuresis alarm has a reported success rate of 50%–70%, and desmopressin has essentially the same efficacy profile as intravesical Botox with a higher relapse rate [1, 21]. It is important to note that if detrusor instability or insufficient functional bladder capacity is a problem at baseline, then the use of the enuresis alarm may be associated with significant distress to the child and family. This not only threatens treatment success, but can also compromise future attempts with the bed alarm once bladder storage issues have been fully resolved [22, 23]. Ultimately, the best choice of therapy is made on a clinical basis, relating to the likely mechanism(s) of nocturnal enuresis (Figure 1).

FIGURE 1.

Pathophysiology of therapeutic targets.

There have been limited studies investigating the efficacy of intravesical Botox injection to treat MNE. A study evaluating children with refractory nocturnal enuresis demonstrated similar efficacy, reinforcing the potential role of intravesical Botox in refractory enuresis [14]. They reported complete response in 58% (29/50) and partial response in 36% (18/50) patients, among a cohort who received either 100iU or 200iU of intravesical Botox. All children had failed to respond to desmopressin and one additional pharmacological therapy (oxybutynin or mirabegron) [14]. In a cohort of 43 children with MNE who received a dose of 100iU complete response was noted in 50% of patients, and partial response in 12.5% [24].

Recent literature has demonstrated the efficacy of intravesical Botox in non‐monosymptomatic nocturnal enuresis (NMNE), with partial or complete resolution of symptoms reported in 25%–26% of cases [24, 25, 26]. From a clinical perspective, the distinction between MNE and NMNE may be more accurately characterised as a penumbra rather than a sharp demarcation, suggesting that these phenotypes share overlapping pathophysiological features in a significant subset of patients.

In the present study, complete success with no relapse two years after treatment was observed in 25% of those who had a complete response to treatment. In those who had a relapse of symptoms, the median duration of response was 11 months. Similarly, other studies have noted a point of weaning of effect (if this is to occur) 12–13 months following treatment [14, 24].

The incidental identification of PUV in 26% of our male cohort reflects a broader clinical reality recently highlighted in the literature: boys with refractory bladder dysfunction have a high prevalence of underlying anatomical pathology. Wagstaff et al. reported a 33% yield for PUV detection in a similar cohort of boys aged 4–16, suggesting that late‐presenting valves are a significant, if often subclinical, contributor to lower urinary tract symptoms [27].

Consistent with their findings, our data showed that valve resection alone was often insufficient for complete resolution, as two of our patients required a subsequent Botox‐only cycle to achieve success. This supports the hypothesis that longstanding, even mild, outflow obstruction may induce changes in detrusor function–such as instability or reduced functional capacity–that necessitate targeted therapy.

It is however impossible to definitively ascertain the effect of intravesical Botox as compared to valve resection in children who had both interventions concurrently. With regard to other treatment strategies and pharmacotherapy, treatment effect was assessed immediately following Botox so treatment effects can be strongly attributed to this (rather than other management strategies employed).

Intravesical Botox has previously been established as a safe treatment in large numbers of children of all ages with functional urinary incontinence [28]. No intra‐operative complications occurred in the current study. Post‐operative complications were mild and self‐resolving, limited to transient haematuria/pain and dysuria in isolated cases, with no instances of urinary tract infection or retention, supporting intravesical Botox as a well‐tolerated, safe procedure.

There are several limitations to the current study. The retrospective nature is a source of reporting or recall bias, particularly in those children who received multiple treatment cycles. To minimise recall bias, the study analysed only response after the most recent and final treatment in the study period. Case numbers were limited by the relative rarity of truly “monosymptomatic” nocturnal enuresis, and larger prospective trials are required to further characterise the efficacy of this intervention, and to define patient groups where this will be most efficacious. Future studies should focus on appraising pre‐operative characteristics—including clinical phenotypes, functional bladder capacity, and sensitivity to first‐line therapies—to identify the specific subset of patients with MNE most likely to achieve treatment success with intravesical Botox. Evaluation of diverse outcomes such as quality of life in future studies would further clarify the effects of intravesical Botox in this cohort.

Intravesical Botox injection is an effective, well‐tolerated and safe treatment option. It is an important component of the multi‐modal options available to treat MNE with a sustained response.

A video demonstrating the injection technique used has been included as Supporting Information for reference.

Author Contributions

All authors have participated in the concept and design; analysis and interpretation of data; drafting or revising of the manuscript, and have approved the manuscript as submitted.

Funding

The authors have nothing to report.

Ethics Statement

The authors declare that the research presented in this manuscript adheres to the ethical principles outlined by the NHMRC National Statement on Ethical Conduct in Human Research. All procedures involving human participants were conducted in accordance with the ethical standards of Cabrini Health and the Declaration of Helsinki (1964), as revised in 2013.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Video S1: Video demonstrating intravesical Botox injection technique.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.