Breaking the vicious circle: Onabotulinum toxin A in children with therapy-refractory dysfunctional voiding

Journal of Pediatric Urology (2015) 11, 119.e1e119.e6

Breaking the vicious circle: Onabotulinum toxin A in children with therapy-refractory dysfunctional voiding L.A. ’t Hoen, J. van den Hoek, K.P. Wolffenbuttel, F. van der Toorn, J.R. Scheepe Department of Pediatric Urology, Sophia Children’s Hospital, Erasmus Medical Center, Rotterdam, The Netherlands Correspondendence to: J.R. Scheepe, Department of Pediatric Urology, Sophia Children’s Hospital, Erasmus Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands, Tel.: þ31107036559; fax: þ31107035632 [email protected] (L.A. ’t Hoen) [email protected] (J. van den Hoek) [email protected] (K.P. Wolffenbuttel) [email protected] (F. van der Toorn) [email protected] (J.R. Scheepe) Keywords Dysfunctional voiding; Therapyrefractory; Botulinum toxin type A; Paediatrics

Abbreviations BTX-AOnabotulinum toxin A; DVDysfunctional voiding; LUTSLower urinary tract symptoms; PVRPost-void residual; UIUrinary incontinence; UTIUrinary tract infection Received 29 July 2014 Accepted 17 October 2014 Available online 25 February 2015

Summary Introduction An increased activity of the external urethral sphincter or pelvic floor muscles during voluntary voiding leads to dysfunctional voiding. Frequently reported symptoms are urinary incontinence, urinary tract infections and high post-void residuals. Dysfunctional voiding is a common problem in school-aged children and despite various treatment options, 10e40% of the children remain therapyrefractory. Objective The aim of this study is to evaluate the effectiveness of Onabotulinum toxin-A (BTX-A) injections in the external urethral sphincter in children with therapyrefractory dysfunctional voiding. Patients and methods Patients with therapy-refractory dysfunctional voiding who have received BTX-A injections in the external urethral sphincter from 2010 to 2013 were analysed. Children with known neuropsychiatric disorders were excluded. All children had abnormal flow patterns and increased pelvic floor tone during uroflowmetry/EMG studies. They had received at least five sessions of urotherapy and two sessions of pelvic floor physical therapy prior to treatment. A total of 100 IU of BTX-A was injected in the external urethral sphincter at the 3, 9 and 12 o’clock positions. Our main outcome measures were urinary incontinence, recurrent urinary tract infections and post-void residual. Results A total of twenty patients, of whom 16 girls, with a median age of 9 years (range 5e14) were treated with BTX-A. The median follow-up was 13 months (range 5e34). Post-void residual decreased by 75% after BTX-A, from a median of 47.5 ml (16.3e88.5 ml) to 0 ml (0.0e28.0 ml) (p Z 0.001) Six patients had a post-void residual < 20 ml prior to treatment. After BTX-A sixteen patients had a postvoid residual <20 ml (Figure). No significant changes in uroflowmetry results was seen. Sixteen children are no longer daily incontinent, of whom 9 became

completely dry (p Z 0.0001). Eleven patients suffered from recurrent urinary tract infections prior to treatment. After BTX-A five children remained infection free, while the other six experienced only one urinary tract infection during follow-up (p Z 0.003). Fourteen patients received additional urotherapy after BTX-A. Repeat injections were necessary in four patients after initial satisfactory results, with repeated good clinical responses. Two children showed no improvement after first BTX-A injection. No serious adverse events were reported. Discussion The results in this homogenous group of patients confirm the conclusions of previous studies in opting BTX-A in the external urethral sphincter to be a viable treatment option for the therapy-refractory group of patients with dysfunctional voiding. What is new, is that in most of our patients post-injection urotherapy was used to amplify the BTX-A effect. During our long-term follow-up the satisfactory results were sustained, similar to the results of the long-term follow-up presented by Vricella et al. [1]. The retrospective character and relative small sample size are limitations of this study. Conclusions This study shows safe and persistent satisfactory results during our average 13-month follow-up in 90% of our patients with therapy-refractory dysfunctional voiding. A prospective study using validated and standardized measurements will be performed to affirm our results and evaluate the exact role of post-injection urotherapy. 1. Vricella GJ, Campigotto M, Coplen DE, Traxel EJ, Austin PF: Long-term efficacy and durability of botulinum-a toxin for refractory dysfunctional voiding in children. J Urol 2014;191:1586e1591.

Figure

Post-void residual n Z 20.

http://dx.doi.org/10.1016/j.jpurol.2014.10.006 1477-5131/ª 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

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Introduction The prevalence of urinary incontinence (UI) at the age of seven years is estimated to be around 7% [1,2]. It is shown that up to 32% of children with UI have dysfunctional voiding (DV) [3]. Dysfunctional voiding is a term used for non-neurogenic increased urethral sphincter or pelvic floor muscle activity during voluntary voiding [4]. This lack of coordination between the detrusor muscle and the urethral sphincter leads to a functional bladder outlet obstruction. Consequently, a vicious circle of UI, UTI and high postvoiding residuals (PVRs) might develop; they are known as signs of DV [5]. Treatment of DV is therefore targeted to break this vicious circle. It involves a multidisciplinary approach and usually starts with behavioural and standard therapy, including: biofeedback therapy, often called urotherapy. Various retrospective studies have shown success rates for urotherapy between 60 and 90% [6e9]. This leaves a substantial group of children with therapy-refractory DV. Currently, there is no evidence-based treatment option for children with therapy-refractory DV. In adults, the usage of botulinum toxin A (BTX-A) in neurogenic patients with detrusor-sphincter dysynergia is a viable option to reduce the functional bladder outlet obstruction [10]. The average duration of the BTX-A effect in the striated muscle of the urethral sphincter is about three months [11]. In recent years, several studies have been conducted into the use of BTX-A for DV in children, and have shown promising results [12e15]. These studies, however, were limited by: patient selection; different forms and doses of botulinum toxin A; botulinum toxin A as the primary treatment; or short follow-up. The present study reports the results of BTX-A injections into the urethral sphincter as treatment for therapy-refractory dysfunctional voiding for a homogenous group of patients beyond the duration of effectiveness of the BTX-A injections.

Material and methods The present study was conducted after receiving approval from the local Medical Research Ethics Committee.

Patients All consecutive children with therapy-refractory DV who received BTX-A injections into the urethral sphincter between 2010 and 2013 were assessed. Dysfunctional voiding is defined as: an abnormal flow pattern and increased pelvic floor tone during uroflowmetry/electromyography (EMG) studies. Children were classified as therapyrefractory if they had they had no signs of improvement after at least five sessions of urotherapy, consisting of timeassisted micturition training, constipation treatment and biofeedback training, as well as at least two sessions of specialised paediatric pelvic-floor physical therapy. The duration of each urotherapy session was 60 min. Patients with neurogenic bladder and previous urological surgical treatment were excluded. Furthermore, patients who received simultaneous BTX-A injections into the detrusor muscle and patients with neuropsychiatric disorders were

L.A. ’t Hoen et al. also excluded. In all patients, an ultrasound investigation was performed to exclude abnormalities of the urinary tract.

Technical procedure Botulinum toxin A injections were administered under general anaesthesia and with antibiotic coverage. For boys, a 9-Fr paediatric offset cystoscope and a 4-Fr injection needle were used. For girls, the transurethral approach to the sphincter is more difficult, therefore a 23-gauge needle was used and injections were placed paraurethral. A total of 100 IU of BTX-A (diluted in 3 ml of saline) were injected in equal amount into the external sphincter at the 3, 9 and 12 o’clock positions.

Outcome measures Outcomes were prospectively recorded in patient medical files. Pretreatment and post-treatment evaluation consisted of patient interviews, voiding diaries, dipstick analysis/urine cultures and uroflowmetry. Post-treatment data were collected for the first time between six and twelve weeks after BTX-A. Results were retrospectively evaluated. The primary outcome was PVR. Secondary outcomes were the symptomatic parameters of UTI and UI episodes, and the uroflowmetric parameters of voiding volume and peak flow rate. To objectify the degree of UI and UTI a threepoint scoring system was adopted. UI was classified as: 1 (never), 2 (incidental) or 3 (daily). A similar classification was used for UTI, with: 1 (never), 2 (once) or 3 (recurrent). UTI was determined to be a complication of the cystoscopy if it developed within the first five days after injection.

Statistical analysis Statistical analysis of the data was performed using SPSS version 21.0 (IBM Corp., Armonk, NY, USA). Continuous data are displayed as the median and interquartile ranges. Ordinal data are presented as the counts and percentages. The Wilcoxon signed-rank test was used to evaluate the difference in outcome measures before and after BTX-A. A two-sided P-value of <0.05 was considered to be statistically significant.

Results A total of 20 children (16 females), with a median age of nine years (range 5e14) were analysed for the present study. These patients had a follow-up ranging from 5 to 34 months, with a median follow-up of 13 months. Table 1 displays the characteristics of the included patients. All patients had an abnormal flow pattern prior to treatment, showing either staccato curves or interrupted curves, with increased EMG activity of the sphincter during the interruption. The change in flow pattern is displayed in Table 1. The main outcome measure, PVR, significantly decreased by 75% from: a median of 47.5 ml (range 16.3e88.5) prior to BTX-A to 0.0 ml (range 0.0e28.0) after BTX-A (P Z 0.001). Six patients had a PVR lower than 20 ml

Breaking the vicious circle: BTX-A in children with DV. Table 1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

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Patient descriptions.

Gender

Age at 1st injection

Repeat injection (months)

Follow-up (months)

Flow pattern pre/post botulinum toxin A

F M F F F F F F M M F F F M F F F F F F

10 8 10 5 5 8 10 10 10 13 10 9 11 7 11 7 5 14 8 10

e 18 20 e e e 11 and 12 e e e e e e e e e 6 e e e

22 24 26 21 20 34 30 6 12 14 11 5 22 8 14 6 9 5 7 7

Staccato/Bell Staccato/Bell Staccato/Bell Interrupted/Bell Staccato/Bell Staccato/Bell Staccato/Bell Staccato/Bell Staccato/Staccato Interrupted/Staccato Staccato/Bell Staccato/Bell Staccato/Bell Interrupted/Bell Staccato/Bell Staccato/Bell Staccato/Bell Staccato/Bell Staccato/Bell Staccato/Bell

before treatment; after treatment this increased to a total of 16 patients. Postvoiding residual (PVR), in percentage of voided volume, significantly decreased after BTX-A (P Z 0.001) (Fig. 1). All patients but one had improved PVR measures. The voided volumes and peak flow rates showed no statistically significant changes compared to prior treatment. The Tzu Chi nomograms were used to evaluate change in peak flow rates; however, this did not show significant changes either [16]. Results are summarised in Table 2. Table 3 shows an assessment of UI and UTI. Initially, all 20 children were incontinent every day. There was a

significant change in incontinence symptoms during followup, with an improvement in 80% of the children (P Z <0.001), of whom, nine remained completely dry. The occurrence of UTI also changed significantly. Eleven children experienced recurrent UTI prior to treatment. During follow-up, five remained infection free, while the other six experienced only one UTI (P Z 0.003). In four children repeat BTX-A injections were necessary after initial satisfactory results at 3 months evaluation. Repeat injections were performed between 6 and 20 months after the first injection. All four children showed a good clinical response to the repeated injections. Two

PVR in % of voided volume

160 140 120 100 80 60 40 20 0 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

PaƟent number Figure 1 Postvoiding residual in percentage of voided volume before and after botulinum toxin A. The blue bars are before and the red bars are after botulinum toxin A. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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L.A. ’t Hoen et al.

Table 2 Uroflowmetry results showing a significantly lower postvoiding residual after botulinum toxin A. The voided volume and peak flow remain unchanged after botulinum toxin A. Median (IQR) Postvoiding residual (PVR) (ml) Voided volume (ml) Peak flow (ml/s)

Table 3

Before botulinum toxin A 47.5 (16.3e88.5) 192.5 (103.5e317.8) 18.0 (12.4e24.6)

After botulinum toxin A 0.0 (0.0e28.0) 203.5 (136.0e298.8) 18.5 (14.3e27.3)

P-value 0.001 0.433 0.600

Results of botulinum toxin A on urinary incontinence and UTI. Incontinence

Daily/Recurrent Incidental/Once Never

Urinary tract infections

Before botulinum toxin A

After botulinum toxin A

Before botulinum toxin A

After botulinum toxin A

20 (100%) 0 0 P-value <0.001

4 (20%) 7 (35%) 9 (45%)

11 (55%) 0 9 (45%) P-value 0.003

0 6 (30%) 14 (70%)

patients did not respond to the initial treatment. Additional urotherapy or paediatric pelvic-floor physical therapy was provided for 14 patients upon request of the physician or the patient. This included three patients with repeat BTX-A treatment. No serious adverse events were reported after BTX-A treatment. One patient experienced a UTI in the first week after receiving BTX-A, which was possibly contributed to the cystoscopy. Nine patients experienced a sudden increase of incontinence five to seven days after treatment. The incontinence improved or resolved spontaneously within three days. One girl described a one-sided numbness of the gluteus maximus muscle. She did not experience any discomfort from this numbness and it spontaneously disappeared within three weeks.

Discussion For the group of therapy-refractory children, an alternative treatment with BTX-A injections into the external urethral sphincter has been explored in recent years. The present study with BTX-A in a homogenous group of patients indicated that BTX-A significantly lowers PVR and substantially reduces symptoms of UI and UTI; these outcomes are long lasting, as evidenced in the patients with a follow-up of more than one year. This suggests that a viable treatment alternative can now be offered to this specific patient group. Results presented in the present study, as seen in the previous studies with different doses, form, or short-term follow-up in children as well [12e15], show that botulinum toxin A treatment continues to be effective for longer than three months e even up to 34 months. The external urethral sphincter is a striated muscle and the expected duration of efficacy of the BTX-A itself is around two to three months [10]. It can be implied that mechanisms other than the BTX-A itself are accountable for this sustainable effect. Dysfunctional voiding comprises a variety of symptoms, which are all reciprocal in their nature, therefore

creating a vicious circle. The elimination of one factor, paralysis of the urethral sphincter with BTX-A, leads to a disruption of this vicious circle. The period in which BTX-A is effective provides an optimal window to improve voiding habits and enables children to regain conscious control of their pelvic floor muscles. Even though PVR significantly decreased after BTX-A and the flow patterns changed to bell-shaped curves in all but two children, no significant changes were found in the other uroflowmetry results after BTX-A. This might be explained by the difference in micturition. The present hypothesis is that due to the functional bladder outlet obstruction, many children with DV void using increased abdominal pressure, which results in high peak flows. The micturition-postponing behaviour could explain the high voiding volumes combined with the high PVRs. After BTX-A, children learn not to postpone micturition and they become able to void without abdominal pressure. A recently published study showed good results during the long-term follow-up [17]. Vricella et al. reported their findings with BTX-A in the urethral sphincter in a group of 12 patients with a median follow-up of 45 months. Although the study by Vricella et al. is comparable with the present study, there are differences in several aspects. First, the patient group in the present study was larger, consisting of 20 children, compared to 12 in their patient group. There are also differences within the patient groups as well. Vricella et al. included four patients with neuropsychiatric problems and four patients who showed abnormalities at ultrasound or vesicourethrogram; the present study included a more homogeneous group of patients without known anatomical abnormalities. Even though the median follow-up was 13 months in the present study, eleven children had a follow-up of more than a year e eight children were even followed beyond 20 months. Twelve of these children received additional post-injection urotherapy and were reported to have improved after BTX-A injections. In addition, out of the four children requiring repeat injections, three children had a follow-up of longer than 24 months. The repeat injections were necessary after

Breaking the vicious circle: BTX-A in children with DV. an average of 13 months, which was similar to the findings of Vricella et al. These findings suggest that a minimal follow-up of 13 months is necessary in children treated with intrasphincteric BTX-A injections. In the present study, a dose of 100 IU of BTX-A was used. No consensus has been reached about which dose will achieve the optimal effect without causing unwanted side-effects. However, the results from the present study and from Vricella et al. [17] showed that 100 IU of BTX-A have positive long-term effects. This makes it a cost-effective dose option compared to the 300 IU described in a previous study [12]. The sudden increase of UI five to seven days after treatment has so far only been reported with the use of Dysport [18] or with a high dosage of BTX-A [12]. The sudden onset of the symptoms can be explained by the working mechanism of BTX-A. Paralysis of the external urethral sphincter is activated after five to seven days, but this does not explain the spontaneous improvement three days later. Franco et al. suggested that children who were actively postponing voiding prior to treatment showed this spontaneous improvement. If they postponed micturition, they would experience UI, due to the paralysis of the external sphincter [12]. This would then support the assumption that BTX-A is able to break the vicious circle by forcing children to adapt their voiding behaviour and consciously regain control of the pelvic floor muscles, or face UI. In 14 patients, BTX-A was combined with urotherapy during the period of efficacy of BTX-A in order to amplify this conscious control of voiding habits. Even though all patients had received extensive treatment of urotherapy and pelvic-floor physical therapy, these patients only showed an improvement after additional treatment with BTX-A injections. Therefore, the effect reported in these children is in all probability due to BTX-A injections. The present study’s results suggest that a combination of urotherapy and BTX-A injections is likely to be more effective than BTX-A injections alone. However, patients and physicians are not offered urotherapy as a standard, which introduces a possible risk for bias. Transient paresis of the gluteus maximus muscle following BTX-A treatment in the external urethral sphincter has not been reported up until now. The reason for the transient paresis still remains up for discussion, even though two hypotheses seem possible. First, the BTX-A solution could have diffused from the external urethral sphincter through to the gluteus maximus muscle. Injection of the BTX-A deep into the pelvic floor muscles could cause diffusion into the lower part of the gluteus maximus muscle. Second, the BTX-A could have reached the gluteus maximus muscle through retrograde transport. The longdistance retrograde transport of BTX-A has already been described in animal models. Cleaved SNAP-25, the result of BTX-A activity, could be observed in the contralateral hemisphere after unilateral injection into the hippocampus [19]. The route of transport could be through the sacral plexus, where both the pudendal nerve and the inferior gluteal nerve originate. The expected duration of effectiveness of BTX-A in the gluteus maximus muscle would be two to three months, because it is a striated muscle; however, in the present case, the numbness disappeared within three weeks. This could be explained by the presumable lower dose of BTX-A, which would have diffused into the gluteus maximus muscle.

119.e5 Knowing that a significant group of children with DV have remained therapy-refractory, and up until recently had no viable treatment options, the consequences of the good long-term results in breaking the vicious circle of DV might be seen throughout adulthood as well. Several studies have investigated the role of childhood UI in relation to lower urinary tract symptoms (LUTS) in adulthood. Adults presenting with nocturnal enuresis show significantly more LUTS during their childhood [20]. Also, childhood daytime incontinence and nocturnal enuresis are associated with adult urge-urinary incontinence [21], especially in young women. If a reliable treatment option can now be offered to this group of therapy-refractory children, this might influence the incidence of LUTS in adults. Limitations of the present study are the relatively small sample size and retrospective nature. Also, the absence of a validated standardised questionnaire in Dutch with which to measure the therapy effects forms a limitation. However, the fact that the present study results are comparable to other studies reinforces the significance of the effects of BTX-A in the external urethral sphincter for children with therapy-refractory DV.

Conclusions Overall, the present study showed that BTX-A is effective in the treatment of dysfunctional voiding. The positive results are sustained in the patients with a follow-up of longer than one year. It is believed that this introduces a viable treatment option for the group of children, who in recent years, have been therapy-refractory and have therefore not been provided with optimal care. The results, which are similar to earlier results, suggest a combination of urotherapy after BTX-A to improve the long-term effectiveness. However, the exact role of post-injection urotherapy is still unclear, and considering the heterogeneous aspect of DV, it is required to further evaluate the effectiveness of BTX-A in a prospective setting using validated and standardised measures.

Conflict of interest None declared.

Funding Stichting Urologisch Wetenschappelijk Onderzoek (SUWO), Rotterdam.

Ethical approval This study was conducted at the Erasmus MC e Sophia Children’s Hospital and was approved by the local Medical Research Ethics Committee (MEC-2012-454).

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