Eﬃcacy and Safety of Botulinum Toxin A for Treating Bladder Hyperactivity in Children and Adolescents with Neuropathic Bladder Secondary to Myelomeningocele

We veri�ed the e�cacy and safety of botulinum toxin A (BTX-A) in treating bladder overactivity in children with neurogenic bladder (NB) secondary to myelomeningocele (MMC). Forty-seven patients (22, females; 25, males; age range, 5–17 years; mean age, 10.7 years) with poorly compliant/overactive neurogenic bladder on clean intermittent catheterization (CIC) and resistance or noncompliant to anticholinergics were injected with 200I� of BTX-A intradetrusor. All patients experienced a signi�cant 66.45 % average increase of leak point volume (Wilcoxon paired rank test = 7.169 e-10) and a signi�cant 118.57 % average increase of speci�c bladder capacity at 20cm H 2 O (Wilcoxon paired rank test = 2.466 e-12). Ten patients who presented with concomitant uni/bilateral grade II–IV vesicoureteral re�ux were treated at the same time with De�ux. No patient presented with major perioperative or postoperative problems. Twenty-two patients needed a second and 18 a third injection of BTX-A aer 6–9 months for the reappearance of symptoms. Aer a mean follow-up of 5.7 years, 38 out of 47 patients achieved dryness between CICs, and 9 patients improved their incontinence but still need pads. Our conclusion is that BTX-A represents a viable alternative to more invasive procedure in treatment of overactive NB secondary to MMC.


Introduction
Current treatment of patients with neurogenic bladder (NB) secondary to myelomeningocele (MMC) is mainly based on the clean intermittent catheterization (CIC) and the associated anticholinergic agents, or on surgical procedures on the bladder or bladder neck. In cases where the NB is characterized by overactivity or low compliance, the �rst safeguard is the use of early anticholinergic drugs, such as oxybutynin, tolterodine, or most recently trospium chloride with the ultimate goal of making the patient dry safeguarding renal function. If anticholinergics and CIC do not provide the desired result, then it is necessary to use more invasive techniques of expansion in order to transform the bladder into a reservoir with high capacity or low pressure [1]. On the basis of recent research, there is an increasingly assertion of the use of botulinum toxin A (BTX-A) in the treatment of NB secondary to MMC as a valid alternative to invasive procedures [2][3][4][5]. We present our experience in a selected group of patients in whom the clinical evaluation and urodynamics assumed the need for action to expand their bladder due to the poor response to drugs, and in whom incontinence and the use of pads between the catheterizations strongly in�uence their social lives.

Methodology
From January 2002 to June 2011, 47 patients out of 68 with neuropathic bladders were selected for BTX-A treatment. ere were 22 females and 25 males (age range: 5-17 years; mean age: 10.7 years) with poorly compliant/overactive bladders on clean intermittent catheterization (CIC) and resistance or noncompliant to pharmacological therapy. Ten patients presented with concomitant uni/bilateral grade II-IV vesicoureteral re�ux (V�R). Despite the treatment, the patients complained of urinary incontinence between catheterizations.  All patients were regularly monitored with periodic urodynamic examinations, voiding cystourethrography, and prophylactic antibiotics. As an imperative condition, there was the requirement that all the patients had negative urine cultures prior to the procedure. e solution used for injection was obtained by preparing 2 vials of BTX-A diluted in 20 cm 3 of 0.9% saline solution for a total of 200 IU, avoiding shaking the vial too roughly. e needle was introduced for 4-5 mm into the bladder wall. e injection was performed by a needle-metallic cannula of 3.7 Ch with 23 G needle of the type used for the correction of re�ux. e needle was introduced for 4-5 mm of its entire length in the bladder wall, and in each site, a quantity of BTX-A of about 1 cm 3 was introduced for a total of 20 injections.
With patients in the lithotomy position, the injection was carried out with the bladder being �lled to about 20% to 30% of its expected capacity. e administration of toxin was carried out in general or local anesthesia in more collaborative patients: in the latter 15 minutes prior to the procedure, 15-25 cm 3 of lidocaine to 0.5% was instilled into the bladder through the catheter. Aer checking the appearance of the bladder and ureteral ostia, then BTX-A was injected according to a blind multipoint procedure. Injections were performed without sparing the trigone, but avoiding periureteral areas in order not to interfere with the ureterovesical dynamics, in 20 different sites taking care not to insert the needle too deeply, especially at the level of the bladder dome for avoiding inadvertently intra-abdominal viscera injection. e appearance of a submucosal ledge was considered a correct injection. When there were trabeculations, they were not spared from the injections as they derived from a focal detrusor hypertrophy. A catheter was kept in place for 24 hours, and an antibiotic was administered for 5 days. In patients with VUR, the correction by endoscopic subureteral injection of De�ux was performed at the end of injections utilizing 1 to 3 cm 3 of bulging agent realizing the so-called total endoscopic management (TEM) [6]. In these latter cases, the antibiotic prophylaxis was maintained for 1 month aer the treatment (Figures 1, 2, and 3).
e follow-up with ultrasound, urodynamics, and clinical evaluation mainly for the dryness was made at 6, 12, and 24 weeks. A VCUG was performed 12 weeks aer the procedure in patients with VUR, and re�ux was considered cured if a complete resolution was obtained or a downgrading to the �rst grade. In case of persistence, the endoscopic injection was repeated. e urodynamic parameters used were leak point pressure and leak point volume (LPP and LPV) and the speci�c bladder capacity at 20 cm H 2 O (SC 20). is index, similar to the compliance, provides a useful functional datum because it indicates the ability of bladder to �ll at low pressure, within the limits of 20 cm H 2 O [7,8]. e values obtained were subjected to statistical Wilcoxon tests for paired ranks.

Dataset Description
e dataset associated with this Dataset Paper consists of one item, which is described as follows. to compliance, this index is especially signi�cant as it shows satisfactory bladder �lling at low pressures. e clinical use of BTX-A is now a common and consolidated technique in several medical �elds. Urology-speci�cally pediatric urology-is an example of its most recent application in neuropathic and nonneuropathic patients [9]. BTX-A blocks acetylcholine release by binding, at the presynaptic level, to SNAP-25, a cytoplasmic protein on the cell membrane, which plays a major role in acetylcholine release [10,11]. e duration of the relaxing effect on the detrusor muscle is not yet known, although the repeated applications-aside from being well tolerated-seem to prolong both duration and efficacy of treatment. Another problem is the most suitable dosage in relation to the characteristics of the detrusor: in our patients, we used 200 IU of BTX-A independently of age and cystometric curve. Dosage was empirically de�ned within a safety margin, based on other reports in the literature; therefore even if our results are satisfactory, further experience in this �eld will most likely help de�ne the most appropriate toxin dosage needed [12][13][14]. Although the small number of patients studied does not allow us to draw de�nite conclusions, the results show that the use of BTX-A can be suitably included in the algorithm for the treatment of neurogenic bladder and detrusor hyperre�exia, aer anticholinergic drugs-or even the �rst treatment in the event of failure of drug treatment. e use of more invasive surgical operations, such as autoaugmentation or enterocystoplasty, could be taken into account only in case BTX-A treatment fails. e range of therapeutic options for this condition can safely include BTX-A treatment, along with anticholinergic drugs and traditional surgery. However, the duration of its efficacy and long-term reliability in urology should be further investigated and standardized, although the experience has shown that the technique can be safely readministered aer 6 months with good results. Moreover,  no relevant side effects were detected aer the administration of BTX-A. is also means that patients require constant clinical and instrumental controls. Another recently highlighted factor concerns the depth of the injection into the bladder. As demonstrated by Mehnert et al. [15] with a study by the use of MRI with toxin labeled with gadolinium, a too deep injection is deposited outside of the bladder wall. erefore, it can be assumed that an ineffective treatment can be linked more to improper depth of the injection rather than to the dosage of toxin. Moreover, there remain uncertain the duration of treatment, the efficacy, and long-term reliability on the bladder. It is not to be underestimated, then, the possibility that repeated dosing of BTX-A may induce the formation of antitoxin antibodies which will void effectiveness [16,17]. Although this event has not yet been described in use on the urinary system, it cannot be excluded that such an event may occur.

Dataset Item 1 (
Our conclusion is that BTX-A represents a viable alternative to more invasive procedure in treatment of NB secondary to MMC, with good objective and subjective results, when anticholinergic agents are not effective or when their side effects lead the patient to abandon the treatment. e procedure allows also the contemporary treatment of VUR decreasing the incidence of renal damage in children on whom conservative management fails to help. However the need for a second and a third treatment is a signi�cant factor in the cost-bene�t assessment [18,19].

Dataset Availability
e dataset associated with this Dataset Paper is dedicated to the public domain using the CC0 waiver and is available at http://dx.doi.org/10.1155/2013/580927/dataset.