Maria Paola Pascali

Effects of botulinum toxin type a in the bladder wall of children with neurogenic bladder dysfunction: a comparison of histological features before and after injections.

PURPOSE Botulinum toxin type A has gained popularity in urology. Most reported studies have been in adults at urology centers and most have addressed long-term safety. Since botulinum toxin type A treatment for neurogenic bladder dysfunction requires repeat injections, verifying that such treatment does not induce fibrosis in children seems essential. MATERIALS AND METHODS The study was approved by the institutional review board and patients were enrolled after we obtained written consent. Patients with neurogenic bladder dysfunction not responding to conventional treatment (anticholinergics and clean intermittent catheterization) were treated with 10 IU/kg botulinum toxin type A up to a maximum of 300 IU. Endoscopic cold cup biopsies were obtained from the posterolateral bladder wall 1.5 to 2 cm above the ureteral orifice. Bladder wall findings were categorized into 3 groups, including inflammatory infiltration, edema and fibrosis. Each criterion was then graded as mild or severe and analyzed by Fishers exact test (p <0.05). RESULTS A total of 46 bladder wall biopsies were obtained from 40 patients 2 to 18 years old. Biopsies were evaluated in groups 1 and 2, including group 1-20 from patients with no botulinum toxin type A injection and group 2-20 after botulinum toxin type A injection. Group 2 was subdivided into group 3-10 biopsies after 1 injection and group 4-10 after multiple injections. Six patients underwent biopsy twice, that is before the first and second treatments. Histological changes were present in all biopsies. When comparing groups 1 and 2, there was no statistically significant difference in inflammation and edema. However, there was a significant difference in fibrosis between groups 1 and 4 (p <0.05) with apparently decreased fibrosis after multiple injections. CONCLUSIONS In our experience repeat botulinum toxin type A injections into the detrusor in children do not lead to increased fibrosis in the bladder wall. This study confirms the long-term safety of botulinum toxin type A in the pediatric population.

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

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.

A cost-of-illness study of spina bifida in Italy

Introduction Spina bifida (SB) is a congenital malformation of the spinal cord, nerves, and adjacent covering structures, with different levels of severity and functional disability. The economic cost of spina bifida and its prevention using folic acid have never been estimated in Italy. This study was conducted to define the cost of illness of SB in Italy. Methods A retrospective multicenter observational study on the social cost of patients with SB was carried out in three SB centers in Italy. Cost data were collected relating to the 12 months preceding the enrollment time (T0), and subsequently 3 months after the T0 time (±20 days) through a case report form designed to collect the relevant information on the costs incurred during the period considered. The data for all patients were analyzed through multivariate analysis on the main parameters. Results We enrolled 128 patients equally divided between males and females, with a mean age of 13 years (minimum, 0; maximum, 29). Diagnosis was mostly postnatal, with 64 cases diagnosed at birth and 33 cases diagnosed subsequently. The lesion severity levels, as defined in the inclusion criteria, were walking (52 patients); walking with simple orthoses (33 patients); walking with complex orthoses (16 patients); and nonwalking, (25 patients). The anatomic type identified is open SB in most cases (84 patients), followed by closed SB (37 patients) and SB occulta (3 patients). The most significant cost per year was for assistive devices, for a total of 4307.00 €, followed by hospitalization (907.00 €), examinations (592.00 €), and drug therapy (328.00 €). Cost breakdown by age range shows that the highest costs are incurred in the 0–4 age range. The highest cost was for cases of open SB (12,103.00 €). The cost/degree of severity ratio showed that the highest cost was for nonwalking patients (14,323.00 €), followed by patients walking with complex orthoses (13,799.00 €). Conclusion The data from this study show that the mean total cost for a patient with SB was 11,351.00 € per year. Based on data provided by the Italian Institute of Health, we can estimate a total annual social cost of about 60 million Euros per year for SB in Italy. Cost of illness was correlated with age and degree of severity of SB.

Re: intradetrusor botulinum neurotoxin A (BoNT-A) injections decrease bladder fibrosis secondary to partial urethral obstruction in the male rat model. Neurourol urodyn 2012;31:564-70.

We have read with great interest this article where the authors have tried to give an explanation of the mechanism of action of BoNTA injections on the bladder wall in an experimental model after a urethral obstruction was created. They mainly investigated the ability of BoNTA to reduce fibrosis as well as contractility and relaxation response. The results of this action are significant, confirming the actions of BoNTA in reducing fibrosis on bladder wall. This risk after repeated BoNTA injections it is still considered a critical point of BoNTA use in humans. The effects of BoNTA on bladder fibrosis was first investigated in adults by Comperat, Apostolidis, Haferkamp, and recently we published the first report in children, showing no significant histopathological changes in the urothelium or smooth muscle, postulating safety of BoNTA in pediatrics. We have continued our study in a large series, comparing specimens obtained over time from the same patient. The study was approved by the local ethics committee and patients were enrolled after written consent was obtained. Patients with neurogenic bladder (NB) were treated with BoNTA, according to this protocol, and received repeated BoNTA injections over time at a mean 12-month interval. Endoscopic cold cup biopsies were obtained from the bladder wall at every treatment. Three criteria were chosen to examine the bladder wall: (a) inflammatory infiltration, (b) edema, and (c) fibrosis. Each criterion was graded as mild or strong, and evaluated using Fischer’s exact test (P < 0.05). Sixty-two bladder wall specimens were obtained from 26 patients, aged 2–18 years old. Group A: 16 patients with 32 specimens obtained before first and second BoNTA treatments; Group B: 10 patients with 30 specimens obtained after 3 different treatments. Histological changes were present in all, but a reduction of fibrosis in the final specimens of Groups A and B (P < 0.05) was observed. According to this result BoNTA safety usage in pediatric urology is confirmed. However, we are not able to explain the reason for the reduced fibrosis that we observed after repeated injections, suggesting that this finding could be related to a better bladder management with decreased detrusor contraction and decreased nerve growth factor production. This experimental study on rodents confirmed the effects of BoNTA in regression of muscle cell degeneration and decreased fibrosis in lamina propria, reducing muscle hypertrophy, and furthermore showed a statistically significant difference between control and BoNTA in term of contractile responses to EFS and carbachol. Many unknown factors still remain to be defined to understand the exact mechanism of action of BoNTA inhibiting muscle contraction related to a block of neurotransmitter release, because BoNTA action may decrease ATP release vesicular, but not Ach release, that is not nonvesicular, directly inhibiting afferent nerve firing. BoNTA does not affect the spontaneous intrinsic contractions of the detrusor and therapeutic effects have to be mediated from a different site: afferent nerves. For these reasons experimental studies of the lower urinary tract such as this one are useful, because they permit advancement in our knowledge, especially regarding the action of new treatments, such as BoNTA, where the mechanism of action is still not completely clarified. Of course we have to critically consider the potential role of animal models in the evaluation of lower urinary tract dysfunction as suggested by Chapple and we have to consider these limitations before translating results to humans. This new experimental study encourages an earlier use of BoNTA in younger children too, as a first line treatment or in other nonneurogenic bladder dysfunctions, as in children operated on for posterior urethral valve, where BoNTA could be useful in order to reduce bladder fibrosis.

Effects of botulinum toxin type a in the bladder wall of children with neurogenic bladder dysfunction: a comparison of histological features before and after injections

Study received institutional review board approval. Supported by the Italian Ministry of Health. * Correspondence: Department of NephroUrology and NeuroUrology Unit, Bambino Gesu 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 gained popularity in urology. Most reported studies have been in adults at urology centers and most have addressed long-term safety. Since botulinum toxin type A treatment for neurogenic bladder dysfunction requires repeat injections, verifying that such treatment does not induce fibrosis in children seems essential. Materials and Methods: The study was approved by the institutional review board and patients were enrolled after we obtained written consent. Patients with neurogenic bladder dysfunction not responding to conventional treatment (anticholinergics and clean intermittent catheterization) were treated with 10 IU/kg botulinum toxin type A up to a maximum of 300 IU. Endoscopic cold cup biopsies were obtained from the posterolateral bladder wall 1.5 to 2 cm above the ureteral orifice. Bladder wall findings were categorized into 3 groups, including inflammatory infiltration, edema and fibrosis. Each criterion was then graded as mild or severe and analyzed by Fisher’s exact test (p 0.05). Results: A total of 46 bladder wall biopsies were obtained from 40 patients 2 to 18 years old. Biopsies were evaluated in groups 1 and 2, including group 1—20 from patients with no botulinum toxin type A injection and group 2—20 after botulinum toxin type A injection. Group 2 was subdivided into group 3—10 biopsies after 1 injection and group 4—10 after multiple injections. Six patients underwent biopsy twice, that is before the first and second treatments. Histological changes were present in all biopsies. When comparing groups 1 and 2, there was no statistically significant difference in inflammation and edema. However, there was a significant difference in fibrosis between groups 1 and 4 (p 0.05) with apparently decreased fibrosis after multiple injections. Conclusions: In our experience repeat botulinum toxin type A injections into the detrusor in children do not lead to increased fibrosis in the bladder wall. This study confirms the long-term safety of botulinum toxin type A in the pediatric population.

VURD Syndrome in a Female

VURD syndrome has been repeatedly described as unilateral reflux into a nonfunctioning renal moiety. This syndrome is considered a pop-off mechanism dissipating pressure in lower urinary tract obstruction: it may be found in association with other protective mechanisms occurring in utero, such as ascites and/or urinomas, and has been exclusively described in male patients. A premature female baby with signs and symptoms of outflow obstruction underwent diagnostic workup revealing congenital urethral hypoplasia with unilateral reflux into a dysplastic kidney. Obstetrical history was positive for early onset, serologically negative ascites without cardiomegaly, which required serial aspirations. Reconstructive surgery was carried out with good results: ascites and VURD syndrome were both deemed to be perinatal protective mechanism against excess pressure in the urinary tract. Although rare, lower urinary tract obstruction in the female can lead to the same protective mechanisms seen in male fetuses/newborns. VURD syndrome and ascites should be interpreted as such and require perinatal specialist counselling.