Onabotulinum toxin A (BONTA ) (Botox, Irvin USA) changed completely the management of neurogenic bladder dysfunction (NBD)in adults and then in children. A 48-week prospective, multicenter, randomized, double-blind phase 3 study, including our center, ruled out  in more than 100 children (age 5–17 years) with NDO and incontinence demonstrated how BONTA injections is safe, well tolerated, effective. According to these results FDA approved Botox bladder injections, in children 5 years and older with neurogenic detrusor overactivity  with no response or intolerance to anticholinergics,  with a max dosage of 200U or ≤ 6U/kg.  Intradetrusor Botox  injections are a highly effective therapy for refractory NDO, but in adults approximately 40% of the patients discontinue treatment over time, for a lack of clinical and/or urodynamic response or because the patients preference. Pediatric data on long-term safety, efficacy, adherence are lacking. For these reasons  we present our 25 years experience with 230 pediatric patients.

All records of patients treated with bladder botox injections since 1997, in our Institution has been evaluated,  Botox has been always considered an off-label  second line treatment, and suggested after failure of standard treatment ( anticholinergics and clean intermittent catheterizations) or where CIC was not accepted or anticholinergics not tolerated . A written consent has been always signed before evaluation and treatment.  
From 2007 a standard  protocol has been defined and still used, but for the new patients treated in  the period of prospective, multicenter, randomized, double-blind phase 3 study. Our protocol , approved by our Ethical Committee, includes endoscopic bladder wall biopsy for edema, inflammation, fibrosis control.
Data regarding age, pathologies, clinical and UD data, histhologic have been recorded during time as number of injections, lapse time between injections, complications , adherence.Botox has been used in the past commonly  at 10UI/kg max 300 UI, with a dosage reduction after approval in adult population ( max 200 UI) in 2011. Data have been evaluated considering 3 period: a) 1997-2007, b) 2008-2011, c) 2011 until 2021.In order to define outcome measures we considered success when  patients reported own  satisfaction plus amelioration of 50%   between : leaking episodes per day (number and degree),Number of pads replaced per day, Post void residual decrease, N° of intermittent catheterism per day, UTI frequency reduction. Kidney ultrasound, UD, serum creatine have been monitored. In this study focus has been established on safety, long term effectiveness and adherence, not reporting urodynamic or histology records that will be considered for future studies.

230 patients aged 1-18 yrs, mean age 8,5 yrs at first injection,  112 males, 118 females, have been treated in our hospital , since 1997 to 2021. 38 pts were treated between 1997-2007, 63 between 2008-2011, 129 from 2012 until December 2021. 45 pts had only 1 injection during time, 49 pts had 2 injections, 40 pts had 3 injections, 26 pts had 4 injections, 15 pts had 5 pts injections, 13 pts had 6 injections, 10 had 7 injections, 16 pts had 8 injections, 3 pts had 9 injections, 8 had 10 injections, 5 pts have been injected more then 10 times (11-22 injections ). 70 pts have been injected more then 5 Times. Lapse between repeated injections has been 6-13 months. 127 pts were treated for Spina Bifida (SB) ( 62 myelomenyngocele, 40 occult spinal dysraphism, 13 lipomenyngocele, 12 caudal regression syndrome), 18 traumatic SCI ,  11 iatrogenic injury,  8 post oncological, 9 myelitis, 46 cerebral palsy and others central injury, 11  valve bladder. Regarding safety in 916 injections  performed in 230 pts no severe intraoperative surgery and anesthesia complications have been reported. All patients have been treated in inpatient regimen, with scheduled postoperative antibiotic, intravenous saline solution hydration, indwelling catheter for 12 hours. In 15 cases, injections, persistent hematuria has been described.5 patients described either limb weakness or generalized fatigue following Botox injection,Effectiveness has been evaluated at 70%, with high success rate, 78% in SCI and SB, lower for CP and posterior urethral valves, 50%. About 230 pts , 31 have been lost at the follow-up. Part of them shifted to other treatment, 32 choose to come back to anticholinergics,  In other  cases there was a request of definitive solution, and for this reason 49 pts performed bladder augmentation, 39 were shifted to sacral neuromodulation and 9 pts died for primary disease complications . Considering adherence ( > 5 treatment) in the remaining 70,  is interesting to note the highest adherence value in SCI, 50%, then SB 33%, with the low data in CP, 20%.

Intradetrusor Botox  injections are a highly effective therapy for refractory NDO. Despite the high percentage fo success there is an high rate of low adherence, where patients require other treatment, less or more invasive. The literature data,  40% of the patients discontinue treatment over time, is light higher respect to our pediatric experience, where we have consider  not only the  lack of clinical and/or urodynamic response but the choice to choose  another treatment, despite  efficacy, could be related to the fact to avoid repeated anesthesia. Different hypothesis have been done to explain  discontinuation rate, first of all  primary and secondary failure. Some mechanisms have been hypothesized to explain long-term failure: formation of neutralizing antibodies and histological modification of the bladder wall. We don't tested antibodies but 
little data exist on the risk o BONTA neutralizing antibodies after bladder injections. Regarding bladder fibrosis  induced during the time of consecutive injections may prevent the normal spread of toxin into the bladder wall and explain secondary failure , our previous data on the histological changes induced by BONTA  intradetrusor injections would suggest that BONTA reduces fibrosis. A critical point remain to establish a correct information with patients and relatives, in order to well explain the advantageof BONTA treatment. In a large series of our patients, BONTA was not able to avoid baller augmentation , performed during time, but has been able to postpone it , after puberty.

On long-term intradetrusor BONTA injections demonstrated to be safe and effective in pediatrics. Neverthless an high percentage  of the patients discontinue treatment over time. A careful follow-up seems useful but BONTA treatment and may be optimized (indication, scheduled injections, etc) . Avoid repeated UD control, in presence of a clinical response, could be useful too with a specific therapeutic education of children and caregiver. Adolescence remains a critical point for low adherence severity of NDO appears to be a significant risk factor for failure, because unsatisfying relatives's expectations.

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Austin PF, Franco I, Dobremez E, et al. OnabotulinumtoxinA for the treatment of neurogenic detrusor overactivity in children. Neurourology and Urodynamics. 2021;40: 493-501. https://doi.org/10.1002/nau.24588

Continence 2S2 (2022) 100437
DOI: 10.1016/j.cont.2022.100437