A Simplified Technique for Botulinum Toxin Injections in Children With Neurogenic Bladder

A Simplified Technique for Botulinum Toxin Injections in Children With Neurogenic Bladder Maria Paola Pascali, Giovanni Mosiello,* Armando Marciano, Maria Luisa Capitanucci, Antonio Maria Zaccara and Mario De Gennaro From the Department of Nephro-Urology, Urodynamics and NeuroUrology Unit, Bambino Gesù Pediatric Hospital, Rome, Italy Abbreviations and Acronyms BoNTA botulinum toxin type A CIC clean intermittent catheterization NBD neurogenic bladder dysfunction Study received ethical committee approval. * Corresponding author: Neurourology Unit, Bambino Gesù Pediatric Hospital, Piazza S Onofrio 4, 00165 Rome, Italy (telephone: 0039.06.68592643; FAX: 0039.06.68592518; e-mail: mosiello@opbg.net). Purpose: Botulinum toxin type A has revolutionized the treatment of neurogenic bladder dysfunction. The original injection technique used a rigid cystoscope and a flexible collagen needle. To date botulinum toxin type A injection techniques have not been standardized. We present our experience in pediatric patients using a new flexible injection system. Materials and Methods: We treated 24 patients 3.8 to 17.5 years old who had neurogenic bladder dysfunction with botulinum toxin type A bladder and/or sphincter injection using a rigid cystoscope and the new N-DO endo-injector needle system. Another 24 patients 3.6 to 17.8 years old were treated with a 3.7Fr standard flexible needle and served as controls. Operative time, hospital stay, complications and efficacy were considered. Selection criteria and treatment were the same in the 2 groups. The 10 IU/kg dose was determined according to European Association of Urology guidelines. Results: All patients received botulinum toxin type A bladder injection while 11 patients in the endo-injector group and 5 controls also received urethral injection. In the endo-injector needle and control groups average operative time was 12.4 and 17.3 minutes for the bladder, and 5.1 and 10.1 minutes for the urethra, respectively (each p 0.05). All patients were discharged home the day after the procedure. No complications were observed. Urodynamics revealed an average maximum detrusor pressure decrease of 25 and 21 cm H 2 O, and an average bladder capacity increase of 75 and 80 ml in the endo-injector and control groups, respectively (p not significant). Conclusions: While retaining efficacy, the endo-injector needle technique appears to be more rapid than the standard procedure for botulinum toxin type A injection for neurogenic bladder dysfunction. Whether patients may be treated with sedation only remains to be clarified. Key Words: urinary bladder, neurogenic; urethra; botulinum toxin type A; injections; endoscopy AS in adults, BoNTA injection is a well established method to treat NBD in children. 1,2 It is currently an alternative when standard therapy with antimuscarinics and CIC fails. 3 Bladder injection techniques have not been standardized to date. 4 In the original application for NBD BoNTA was administered through a rigid cystoscope. Less invasive techniques have already been reported, such as the Dasgupta technique, which uses ultrafine injection needles via a flexible cystoscope with the patient under local anesthesia and injections evenly distributed in the bladder wall apart from the trigone. 2558 www.jurology.com 0022-5347/11/1856-2558/0 Vol. 185, 2558-2562, June 2011 THE JOURNAL OF UROLOGY Printed in U.S.A. 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI:10.1016/j.juro.2011.01.037

SIMPLIFIED BOTULINUM TOXIN INJECTION TECHNIQUE FOR NEUROGENIC BLADDER 2559 Figure 1. Map of bladder injections Our experience started in 1997 with BoNTA for neuropathic bladder secondary to myelomeningocele, occult spina bifida and spinal cord injury. The urodynamic patterns included were overactive bladder with dyssynergia or a high pressure, low compliant bladder in patients who did not satisfactorily respond to anticholinergics. Although the original technique described by Schurch et al of performing injections at multiple sites using a rigid cystoscope and flexible needle is long established, 5 since 2003 we have defined our personal technique and treatment protocol. In this study we evaluated the benefit of a flexible needle system 6 with a rigid cystoscope to inject BoNTA in a pediatric population. MATERIALS AND METHODS Informed consent was obtained from patients and/or parents entering the study. The study was done in accordance with the Declaration of Helsinki in a protocol for the use of BoNTA in children with NBD, as approved by our ethical committee. All patients were on CIC, and had no response to standard treatment with anticholinergics and no vesicoureteral reflux. Study exclusion criteria were age less than 2 years, previous lower urinary tract surgery, unstable neurological status or urinary tract infections. In all patients had urodynamic examination was performed 3 months before treatment and 3 to 6 months thereafter. All examinations were done according to International Children s Continence Society standards. 7 Incontinence was evaluated before and after treatment based on pad use and patient diary reports. To define changes in dry episodes or dryness between catheterizations before and after BoNTA treatment we also graded dryness status as 0 completely dry, 1 no pads and urine leakage only during the night, 2 usually no pads but 1 or more urinary leakage episodes during the day and 3 pads used due to urinary leakage almost every time. 5,8 The effectiveness of continence treatment was established at the 3-month follow-up and considered cure or improvement in dryness. All patients were treated with BoNTA at dose of 10 IU/kg (maximum 300 IU Botox ). Technique Procedures consisted of multiple injections into the detrusor following vertical virtual lines, including 2 starting 0.5 to 1 cm above and lateral to the urethral orifices, and the others in the middle (fig. 1), sparing the trigone and blood vessels. A rigid cystoscope was used with the patient under general anesthesia and the procedure was always done in the operating room. Injections were made preferably into a trabeculated muscle bundle by injecting 1 ml (10 IU/1 ml saline solution) at each site with an injection depth of 3 to 5 mm and a full bladder. 9,10 When BoNTA injections were performed on the bladder wall or the sphincter, the same dose of 10 IU/kg was used, including 8 IU/kg for the bladder and 2 IU/kg for the urethra. Transurethral injections were performed deeply at the level of the external striated sphincter at the 3, 6 and 9 o clock positions. Postoperatively in all patients a Foley catheter was left in situ for 12 hours and CIC was started thereafter. Feeding started 2 hours after the end of the operative procedure with intravenous fluid administration for 12 hours. To exclude side effects, vital signs (temperature, heart rate and oxygen saturation) were recorded in all patients. Patients were discharged home the following day. Antibiotics were prescribed for 7 days and anticholinergics were discontinued in all after 2 weeks. Before the procedures patients were allocated into 2 treatment groups. Group 1 was treated with the new N-DO endo-injector system with a 5Fr flexible catheter needle that is adjustable in curving geometry and length (fig. 2). Group 2 was treated with a classic 3.7Fr flexible collagen needle. The N-DO system is a new endo-injector with a progressively curving, retractable needle that has some technical advantages. This 5Fr flexible needle enables easier injection at different areas in a controlled Figure 2. A, endo-injector system with needle length handle control. B, retractable needle.

2560 SIMPLIFIED BOTULINUM TOXIN INJECTION TECHNIQUE FOR NEUROGENIC BLADDER Figure 3. Endoscopic procedure. A, needle retracted before injection. B, injecting trabeculated muscle bundles. mode due to the slider on the handle, which allows the operator to extend the needle to the desired length, retract it after injection and control injection depth as desired since needle length can be adjusted 2 mm at a time. This is useful for bladder injection, for which it is possible to define a standard 4 mm depth (2 steps). In contrast, for urethral injection it is possible to inject more deeply at the external urethral sphincter level. Needle curvature provides easier access to areas where injection is usually difficult, such as the lateral or superior bladder wall, or the bladder neck, and also makes it possible to always inject on the trabeculated muscle bundle. The system keeps the needle visible at all times for safety, effectiveness, precision and control (fig. 3). Retracting the needle during bladder inspection may avoid unwanted bladder wall puncture, minimizing the risk of complications even in inexperienced hands. To evaluate results in the 2 groups we compared endoscopic procedure duration, hospital stay, complications and effectiveness with respect to continence status, and preoperative and postoperative urodynamic records. Data were analyzed using standard statistical Microsoft Excel with the Student t, chi-square and Fisher exact tests with p 0.05 considered statistically significant. RESULTS A total of 48 patients were enrolled in the study and assigned to group 1 24 who were 3.8 to 17.5 years old with the endo-injector needle system and control group 2 24 who were 3.6 to 17.8 years old with the standard 3.7Fr collagen needle. All patients underwent bladder wall treatment while 11 in group 1 and 5 in group 2 were also treated on the bladder neck and urethra. In groups 1 and 2 complete mean operative time was 12.4 and 17.3 minutes for the bladder, and 5.1 and 10.1 minutes for the urethra, respectively (each p 0.05). All procedures were done in the operating room using general anesthesia. Postoperative management was the same in the 2 groups. Hospital stay did not differ in the groups and all patients were discharged home the day after the procedure with no complications. Procedure effectiveness in terms of urodynamic data, dryness rate improvement/cure and mean duration of effect showed no statistically significant difference in the 2 groups (see table). DISCUSSION Since the first report in 2002 by Schulte-Baukloh on 17 patients with NBD related to spina bifida, 11 BoNTA has demonstrated its effectiveness in the pediatric population. 11 There has been increasing evidence of BoNTA use in children with NBD during the years. 12 18 Nevertheless, the injection technique has not been standardized in children or adults. Although BoNTA administration using a flexible or rigid cystoscope has been reported with significant improvement in symptoms and urodynamic parameters, 19,20 to our knowledge no comparative studies have defined the advantages of different techniques. Originally BoNTA was administered using a rigid cystoscope and a collagen flexible needle. Subsequently a minimally invasive technique using a flexible cystoscope 21 became popular in adults, in whom BoNTA administration is often performed using local anesthesia or sedation. 22 In the pediatric population there is no clear consensus on the optimal dose, injection number and sites or cystoscope type. The amount of Botox injected into the bladder was 5 to 12 IU/kg with a Urodynamic and clinical results Group 1 Group 2 Mean change: Detrusor pressure (cm H 2 O) 25 21 Bladder capacity (ml) 75 80 % Incontinence cure/improvement 75 69 Mean mos benefit (range) 8.2 (6.1 12.9) 8.1 (6.2 12.5)

SIMPLIFIED BOTULINUM TOXIN INJECTION TECHNIQUE FOR NEUROGENIC BLADDER 2561 maximal dose of 360 IU, usually at 30 injection sites (range 10 to 50) of 10 IU/ml (range 10 kg/20 ml to 12/15). The most commonly used Botox dose is 10 IU/kg/ml with a maximal dose of 300 IU and a maximum of 30 injections. In all pediatric studies injection as been done directly into detrusor, sparing the trigone, using a rigid cystoscope and general anesthesia, as in our experience. For sphincteric/bladder neck applications the injections are usually performed at the 3, 6 and 9 o clock positions transurethrally or transperineally with a dose of 50 to 100 IU depending on patient age and body weight. 1,2 Instrument choice is related to instrument availability and individual experience with pediatric urologists mainly using a rigid instead of a flexible cystoscope. In 2003 we started to use the N-DO injection system with a 5Fr 24 gauge needle instead of the flexible collagen or metallic 3.7Fr 23 gauge needle that we used previously, always with a rigid cystoscope, to treat NBD with BoNTA. We performed combined bladder and urethral injections in some children who could not or refused to perform CIC without any obvious beneficial effects on dry episodes. BoNTA urethral/bladder neck injections produce transient chemical sphincterotomy. It can be used safely for detrusor-sphincter dyssynergia, as in adolescents with partially preserved micturition who prefer to use abdominal straining to void instead of CIC due to common transient refusal of the catheterization treatment regimen, or in severely disabled obese patients as an alternative to female urethral over distension or male endoscopic external sphincterotomy 23 in all in whom there is no clinical indication to create a continent catheterizable stoma. In our experience we have always used the same technique and protocol to inject the bladder and urethra with same dose (10 IU/kg), dilution (10 IU/ ml) at the same site, sparing the trigone and following rows in the bladder, and at the 3, 6 and 9 o clock positions in the urethra. We evaluated the theoretical advantages of a new needle. Although we noted equal effectiveness and safety, our results showed a significant difference in the 2 groups in operative time (p 0.05). This decreased operative time seems to be useful for 2 main reasons. 1) It encourages combined intradetrusor and intrasphincter injections, which may achieve better results for upper urinary tract protection and maybe relative dryness, as suggested. 24 2) It makes BoNTA amenable to administration using local anesthesia or using sedation as in adults, in the outpatient setting, decreasing hospital stay and costs. 25 CONCLUSIONS Today BoNTA administration is a well established treatment for NBD in children. Our technique with this injection system seems to be safe and effective, encouraging more correct treatment of the bladder or urethra with no morbidity. Decreased operative time may allow BoNTA to be administrated using local anesthesia or sedation even in the pediatric population, reducing hospital stay and costs. ACKNOWLEDGMENTS Dr. Stefano Canu assisted with statistical analysis. REFERENCES 1. Gamé X, Mourdacade P, Chartier-Kastler E et al: Botulinum toxin-a intradetrusor injections in children with neurogenic detrusor overactivity/neurogenic overactive bladder. A systematic literature review. J Pediatr Urol 2009; 5: 156. 2. Dasgupta R and Murphy FL: Botulinum toxin in pediatric urology: a systematic literature review. Pediatr Surg Int 2009; 25: 19. 3. Hernandez RD, Hurwitz RS, Foote JE et al: Nonsurgical management of threatened upper urinary tracts and incontinence in children with myelomeningocele. J Urol 1994; 152: 1582. 4. Apostolidis A, Dasgupta P, Denys P et al: Recommendations on the use of Botulinum Toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunction: a European consensus report. Eur Urol 2009; 55: 100. 5. Schurch B, Sthohrer M, Kramer G et al: Botulinum toxin type A for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergics drugs? Preliminary results. J Urol 2000; 164: 692. 6. Brausi AM, Verrini G, De Luca G et al: The use of local anaesthesia with N-DO injector for transurethral resection of bladder tumors: preliminary results and cost effectiveness analysis. Eur Urol 2007; 52: 1407. 7. Nevéus T, von Gontard A, Hoebeke P et al: The standardization of terminology of lower urinary tract function in children and adolescent: report from the Standardisation Committee of the International Children s Continence society. J Urol 2006; 176: 314. 8. Kuo HC: Urodynamic evidence of effectiveness of botulinum toxin-a injection in the treatment of detrusor overactivity refractory to anticholinergics agents. Urology 2004; 63: 868. 9. Schulte-Baukloh H, Knispel HH et al: A minimally invasive technique for outpatient local anaesthetic administration of intradetrusor botulinum toxin in intractable detrusor overactivity. BJU Int 2005; 95: 454. 10. Apostolidis A, Dasgupta R, Fowler CJ et al: Re: A minimally invasive technique for outpatient local anaesthetic administration of intradetrusor botulinum toxin in intractable detrusor overactivity. BJU Int 2005; 95: 917. 11. Schulte-Baukloh H, Schobert MT, Stolze T et al: Efficacy of botulinum-a toxin in children with detrusor hyperreflexia due to myelomeningocele: preliminary results. Urology 2002; 59: 325. 12. Schulte-Baukloh H, Michael T, Sturzebecher B et al: Botulinum-A toxin detrusor injection as a novel approach in the treatment of bladder spasticity in children with neurogenic bladder. Eur Urol 2003; 44: 139. 13. Riccabona M, Koen M, Schindler M et al: Botulinum-A toxin injection into the detrusor: a safe alternative in the treatment of children with my-

2562 SIMPLIFIED BOTULINUM TOXIN INJECTION TECHNIQUE FOR NEUROGENIC BLADDER elomeningocele with detrusor hyperreflexia. J Urol 2004; 171: 845. 14. Schulte-Baukloh H, Knispel HH, Stolze T et al: Repeated botulinum-a toxin injections in treatment of children with neurogenic detrusor overactivity. Urology 2005; 66: 865. 15. Akbar M, Abel R, Seyler TM et al: Repeated botulinum-a toxin injections in the treatment of myelodysplastic children and patients with spinal cord injuries with neurogenic bladder dysfunction. BJU Int 2007; 100: 639. 16. Altaweel W, Jednack R, Bilodeau C et al: Repeated intradetrusor botulinum toxin type A in children with neurogenic bladder due to myelomeningocele. J Urol 2006; 175: 1102. 17. Kajbafzadeh AM, Moosavi S, Tajik P et al: Intravesical injection of botulinum toxin type A: management of neuropathic bladder and bowel dysfunction in children with myelomeningocele. Urology 2006; 68: 1091. 18. Neel KF, Soliman S, Salem M et al: Botulinum-A toxin: solo treatment for neuropathic noncompliant bladder. J Urol 2007; 78: 2593. 19. Schurch B, de Seze M, Denys P et al: Botulinum toxin type A is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-mo study. J Urol 2005; 174: 196. 20. Apostolidis A, Kalsi V, Gonzales G et al: A comparison between the response of patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity to the first intradetrusor injection of botulinum-a toxin. J Urol 2005; 174: 984. 21. Harper M, Popat R, Dasgupta R et al: A minimally invasive technique for outpatient local anaesthetic administration of intradetrusor botulinum toxin in intractable detrusor overactivity. BJU Int 2003; 92: 325. 22. Smith PC and Chancellor MB: Simplified bladder botulinum-toxin delivery technique using flexible cystoscope and 10 sites injection. J Endourol 2005; 19: 880. 23. de Jong TPM, Chrzan R, Klijn AJ et al: Treatment of neurogenic bladder in spina bifida. Pediatr Nephrol 2008; 23: 889. 24. Safari S, Jamall S, Habibollahi P et al: Intravesical injection of botulinum toxin type A for management of neuropathic bladder: a comparison of two methods. Urology 2010; 76: 225. 25. Sangster P and Kalsi V: Health economics and intradetrusor injections of botulinum for the treatment of detrusor overactivity. BJU Int, suppl., 2008, 102: 17.